Antiemetic extended release solid dosage forms

ABSTRACT

A pharmaceutical formulation includes (1) a first dosage component comprising: a core comprising a non-ionic polymer matrix, a first amount of ondansetron or an equivalent amount of an ondansetron salt thereof dispersed within the matrix, and an electrolyte dispersed within the matrix; a first seal coat surrounding the core, the first seal coat comprising a non-ionic polymer matrix; and an immediate release drug layer surrounding the first seal coat, wherein the immediate release drug layer comprises a non-ionic polymer and a second amount of ondansetron or an equivalent amount of an ondansetron salt thereof dispersed therein; and (2) a second dosage component comprising: a core comprising a third amount of ondansetron or an equivalent amount of an ondansetron salt thereof, at least one filler, and a lubricant; and a coating surrounding the core, the coating comprising water and a mixture of methacrylic acid-alkyl acrylate copolymers with alkaline groups.

RELATED APPLICATION

This application is a continuation of U.S. application Ser. No. 14/212,954, filed Mar. 14, 2014, which claims the benefit of and priority to U.S. provisional Application Ser. No. 61/782,395, filed Mar. 14, 2013, the entire disclosure of each of which is incorporated by reference in their entirety.

BACKGROUND

The 5-HT₃ antagonists are a class of drugs that act as receptor antagonists at the 5-HT₃ receptor, a subtype of serotonin receptor found in terminals of the vagus nerve and in certain areas of the brain. With the notable exception of alosetron and cilansetron, which are used in the treatment of irritable bowel syndrome, all 5-HT₃ antagonists are antiemetics, used in the prevention and treatment of nausea and vomiting. They are particularly effective in controlling the nausea and vomiting produced by cancer chemotherapy and are considered the gold standard for this purpose. Ondansetron is a serotonin 5-HT₃ receptor antagonist used alone or with other medications to prevent nausea and vomiting, and is used for preventing nausea and vomiting caused by cancer drug treatment (chemotherapy) and radiation therapy. It is also used to prevent and treat nausea and vomiting after surgery.

SUMMARY

Extended release solid dosage forms are disclosed herein. More particularly, antiemetic extended release solid dosage forms are disclosed herein for preventing nausea and vomiting.

According to aspects illustrated herein, there is disclosed a pharmaceutical formulation that includes (1) a first dosage component comprising: a core comprising a non-ionic polymer matrix providing sustained release, a first amount of ondansetron or an equivalent amount of an ondansetron salt thereof dispersed within the matrix, and an electrolyte dispersed within the matrix; a first seal coat surrounding the core, the first seal coat comprising a non-ionic polymer matrix; and an immediate release drug layer surrounding the first seal coat, wherein the immediate release drug layer comprises a non-ionic polymer and a second amount of ondansetron or an equivalent amount of an ondansetron salt thereof dispersed therein; and (2) a second dosage component comprising: a core comprising a third amount of ondansetron or an equivalent amount of an ondansetron salt thereof, at least one filler, and a lubricant; and a coating surrounding the core, the coating comprising water and a mixture of methacrylic acid-alkyl acrylate copolymers with alkaline groups. In an embodiment, the coating of the second dosage component comprises: from about 30% (w/w) to about 55% (w/w) of purified water; from about 25% (w/w) to about 45% (w/w) of Eudragit® RS 30D; from about 3.0% (w/w) to about 25% (w/w) of Eudragit® RL 30D; and from about 1.0% (w/w) to about 6.0% (w/w) of talc. In an embodiment, the pharmaceutical formulation is sufficiently designed to meet the two stage test dissolution profile in a basket apparatus: (a) release of not more than 25% of the total amount of ondansetron in 2 hours in an acid stage comprising 900 ml 0.1N HCl at 50 rpm; and (b) release of not less than 40% of the total amount of ondansetron in 30 hours in 900 ml phosphate buffer pH 6.8 at 50 rpm following the acid stage.

According to aspects illustrated herein, there is disclosed a packaged pharmaceutical preparation that includes a plurality of the pharmaceutical formulations of the present invention in a sealed container and instructions for administering the pharmaceutical formulations orally to effect prevention of nausea and vomiting

According to aspects illustrated herein, there is disclosed a pharmaceutical preparation that includes a plurality of the pharmaceutical formulations of the present invention each in a discrete sealed housing, and instructions for administering the pharmaceutical formulations orally to effect prevention of nausea and vomiting.

According to aspects illustrated herein, there is disclosed a method for reducing side effects of chemotherapy treatment that includes administering a pharmaceutical formulation of the present invention to a patient, wherein side effects including nausea and vomiting are reduced after an amount of ondansetron has been released from the pharmaceutical formulation, is absorbed by the patient, and reaches the systemic circulation of the patient.

According to aspects illustrated herein, there is disclosed an extended release ondansetron tablet that includes a core comprising a hydrophilic swellable matrix comprising ondansetron, or a pharmaceutically acceptable salt thereof, and sodium citrate anhydrous; a first seal coating comprising hypromellose and plasACRYL™; an immediate release drug layer surrounding the first seal coating comprising ondansetron, or a pharmaceutically acceptable salt thereof, hypromellose and plasACRYL™; and a second seal coating comprising hypromellose and plasACRYL™ T20, wherein the immediate release layer is sufficiently designed to release about ¼ of a total dose of ondansetron within about 1 hour after oral administration, and wherein the core is sufficiently designed to release the remaining dose of ondansetron for a period of up to 24-hours via zero-order release. In an embodiment, the core comprises about 18 mg of ondansetron free base. In an embodiment, the core comprises about 20 mg of ondansetron free base. In an embodiment, the core comprises about 28 mg of ondansetron free base. In an embodiment, the sodium citrate anhydrous is present at a concentration in the range of about 50% to about 100% by weight of the hydrophilic swellable matrix. In an embodiment, the hydrophilic swellable matrix of the core is METHOCEL™ K4M Premium CR, the hypromellose of the first seal coating and the second seal coating is METHOCEL™ E5 Premium LV, and the hypromellose of the immediate release drug layer is METHOCEL™ E5 Premium LV. In an embodiment, the immediate release layer comprises about 6 mg of ondansetron.

According to aspects illustrated herein, there is disclosed an extended release solid dosage form that includes an internal portion, wherein the internal portion comprises a first dose of at least one serotonin antagonist; a first coating, wherein the first coating directly encapsulates the internal portion of the solid dosage form; a drug layer coating, wherein the drug layer coating directly encapsulates the first coating, wherein the drug layer coating comprises a second dose of the at least one serotonin antagonist, wherein the drug layer coating is at least 4%, by weight, of the solid dosage form, wherein the second dose is equal to at least 15%, by weight, of a total dose of the at least one serotonin antagonist in the solid dosage form, and wherein the first dose is equal to the total dose minus the second dose; and a second coating, wherein the second coating directly encapsulates the drug layer coating, wherein the internal portion has solubility in water of X, wherein the first coating, the drug layer coating, and the second coating have solubility in water of at least Y, and wherein X is less than Y. In an embodiment, the at least one serotonin-3 receptor antagonist is ondansetron hydrochloride. In an embodiment, the second dose is equal to at least 20%, by weight, of the total dose of the at least one serotonin-3 receptor antagonist in the solid dosage form. In an embodiment, the at least one serotonin-3 receptor antagonist is ondansetron hydrochloride. In an embodiment, the second dose is equal to at least 25%, by weight, of the total dose of the at least one serotonin-3 receptor antagonist in the solid dosage form. In an embodiment, the first coating and the second coating comprise a hydrophilic material. In an embodiment, the drug layer further comprises a hydrophilic material. In an embodiment, the hydrophilic material is hypromellose. In an embodiment, the first coating and the second coating are each of at least 1.5%, by weight, of the solid dosage form. In an embodiment, the ratio of the hypromellose to the at least one serotonin-3 receptor antagonist in the drug layer is about 4:6. In an embodiment, a total amount of hypromellose in the first coating, the drug layer, and the second coating is less than 4%, by weight, of the solid dosage form. In an embodiment, the core further comprises sodium citrate in an amount of less than 15%, by weight, of the core. In an embodiment, X is sufficiently less than Y so that the second dose is substantially released from the solid dosage form within less than 12 hours after the solid dosage form is exposed to an aqueous environment, and the first dose is substantially released from the solid dosage in a zero-order release profile over a period of 12 to 24 hours after the solid dosage form is exposed to the aqueous environment. In an embodiment, the aqueous environment has a pH in the range of pH 1.5 to pH 7.5. In an embodiment, the solid dosage form is compressed into a tablet. In an embodiment, the solid dosage form is formed as a capsule. In an embodiment, the core further comprises glycine in an amount of less than 20%, by weight, of the core.

According to aspects illustrated herein, there is disclosed an extended release ondansetron tablet made by compressing a sustained release core tablet and then coating the core tablet with a first seal coat followed by drug coat and finally a second seal coat, wherein the core tablet comprises a hydrophilic swellable matrix comprising ondansetron hydrochloride and sodium citrate anhydrous, wherein the first seal coat comprises comprising hypromellose and plasACRYL™, wherein the drug coat comprises ondansetron hydrochloride, hypromellose and plasACRYL™, and wherein the second seal coat comprises hypromellose and plasACRYL™ T20.

According to aspects illustrated herein, there is disclosed a solid oral dosage form that includes a core comprising a non-ionic polymer matrix, a first amount of a first antiemetic drug or a pharmaceutically acceptable salt thereof dispersed within the matrix, and a salt dispersed within the matrix; a first seal coat surrounding the core, wherein the first seal coat is comprised of a non-ionic polymer matrix; and an immediate release drug layer surrounding the first seal coat, wherein the immediate release drug layer comprises a non-ionic polymer and a second amount of a second antiemetic drug or a pharmaceutically acceptable salt thereof dispersed therein, wherein the drug layer is sufficiently designed to release the second amount of the antiemetic drug over a period of at least 1 hour, wherein the solid oral dosage form is sufficiently designed to release the first amount of the first antiemetic drug and the second amount of the second antiemetic drug over a minimum period of 16 hours.

According to aspects illustrated herein, there is disclosed a solid oral dosage form that includes a core comprising hypromellose, 18 mg of ondansetron or an equivalent amount of an ondansetron salt thereof, and sodium citrate anhydrous; a first seal coat surrounding the core and comprising hypromellose; and an immediate release drug layer surrounding the first seal coat and comprising hypromellose and 6 mg of ondansetron or an equivalent amount of an ondansetron salt thereof, the immediate release drug layer sufficient to release the ondansetron over a period of at least 1 hour, wherein the total amount of ondansetron in the dosage form is released over 24 hours.

According to aspects illustrated herein, there is disclosed a solid oral dosage form that includes a core comprising a non-ionic polymer matrix, a first amount of ondansetron or an equivalent amount of an ondansetron salt thereof dispersed within the matrix, and a salt dispersed within the matrix; a first seal coat surrounding the core, wherein the first seal coat is comprised of a non-ionic polymer matrix; and an immediate release drug layer surrounding the first seal coat, wherein the immediate release drug layer comprises a non-ionic polymer and a second amount of ondansetron or an equivalent amount of an ondansetron salt thereof dispersed therein, wherein the solid oral dosage form results in an in vitro ondansetron dissolution profile when measured in a type 2 paddle dissolution apparatus at 37° C. in aqueous solution containing distilled water at 50 rpm that exhibits: a) from about 20% to 50% of the total ondansetron is released after two and a half hours of measurement in the apparatus; b) from about 50% to 70% of the total ondansetron is released after five hours of measurement in the apparatus; and c) no less than about 90% of the total ondansetron is released after fifteen hours of measurement in the apparatus.

According to aspects illustrated herein, there is disclosed a packaged pharmaceutical preparation that includes a plurality of the solid oral dosage forms of the present invention in a sealed container and instructions for administering the dosage forms orally to effect prevention of nausea and vomiting

According to aspects illustrated herein, there is disclosed a pharmaceutical preparation that includes a plurality of the solid oral dosage forms of the present invention each in a discrete sealed housing, and instructions for administering the dosage forms orally to effect prevention of nausea and vomiting.

According to aspects illustrated herein, there is disclosed a method for controlling nausea and vomiting that includes administering a solid dosage form of the present invention to a patient, wherein nausea and vomiting are controlled after an amount of ondansetron has been released from the solid dosage form, is absorbed by the patient, and reaches the systemic circulation of the patient.

According to aspects illustrated herein, there is disclosed a method for reducing side effects of chemotherapy treatment that includes administering a solid dosage form of the present invention to a patient, wherein side effects including nausea and vomiting are reduced after an amount of ondansetron has been released from the solid dosage form, is absorbed by the patient, and reaches the systemic circulation of the patient.

According to aspects illustrated herein, there is disclosed a method for reducing side effects of motion sickness that includes administering a solid dosage form of the present invention to a patient, wherein side effects including nausea and vomiting are reduced after an amount of ondansetron has been released from the solid dosage form, is absorbed by the patient, and reaches the systemic circulation of the patient.

According to aspects illustrated herein, there is disclosed a method for reducing side effects of anesthetics that includes administering a solid dosage form of the present invention to a patient after the patient has been exposed to an anesthetic, wherein side effects including nausea and vomiting are reduced after an amount of ondansetron has been released from the solid dosage form, is absorbed by the patient, and reaches the systemic circulation of the patient.

BRIEF DESCRIPTION OF THE DRAWINGS

The presently disclosed embodiments will be further explained with reference to the attached drawings. The drawings shown are not necessarily to scale, with emphasis instead generally being placed upon illustrating the principles of the presently disclosed embodiments.

FIG. 1 shows a process flow diagram for formulating extended release ondansetron hydrochloride lot numbers L004-04001, -04003, -04005, -04007 and -04009 of an embodiment of the present disclosure.

FIG. 2 shows a process flow diagram for formulating extended release chronodosed ondansetron hydrochloride lot numbers L004-04002, -04004, -04006 and -04008 of an embodiment of the present disclosure.

FIG. 3 shows a process flow diagram for seal coat solution preparation of an extended release dosage form of an embodiment of the present disclosure.

FIG. 4 shows a process flow diagram for enteric coat suspension preparation of an extended release dosage form of an embodiment of the present disclosure.

FIG. 5 shows a process flow diagram for immediate release layer suspension preparation of an extended release dosage form of an embodiment of the present disclosure.

FIG. 6 shows a process flow diagram for chronodosed suspension preparation for lot numbers L004-04002A to -04002E of an embodiment of the present disclosure.

FIG. 7 shows a process flow diagram for chronodosed suspension preparation for lot numbers L004-04002F to -04002J, -04004A to -04004D, -04006A to -04006F and for -04008A and -04008B of an embodiment of the present disclosure.

FIG. 8 shows the dissolution profiles for Ondansetron bimodal tablets, 28 mg L004-04001 and -04001A, and Ondansetron bimodal tablets 36 mg -04003.

FIG. 9 shows the dissolution profile for Ondansetron core tablets 28 mg L004-04005.

FIG. 10 shows the dissolution profiles for Ondansetron core tablet L004-007 28 mg and Ondansetron bimodal tablets 36 mg -04007A.

FIG. 11 shows the dissolution profiles (in mg) for Ondansetron bimodal tablets, 28 mg L004-004001 and -04001A, and Ondansetron bimodal tablets 36 mg L004-04003, -04007A and -04007B.

FIG. 12 shows the dissolution profiles (in mg/time) of the Ondansetron bimodal drug products L004-04003, -04007A, -04007B, -04009A and -04009B.

FIG. 13 shows the dissolution profiles (in %) for Ondansetron bimodal drug products L004-04003, -04007A, -04007B, -04009A and -04009B.

FIG. 14 shows the dissolution profiles (in %) for Ondansetron bimodal tablets, 28 mg L004-04001 and -04001A, and Ondansetron bimodal tablets 36 mg -04003, -04007A and -04007B.

FIG. 15 shows the dissolution profiles for chronodosed Ondansetron tablets, 8 mg L004-04002D, -04002D-04002HC, -04002E, -04002F-2HC and -04002J.

FIG. 16 shows the dissolution profiles for chronodosed Ondansetron tablets, 8 mg L004-04004A to -04004D.

FIG. 17 shows the dissolution profiles for chronodosed Ondansetron tablets, 8 mg L004-04006A to -04006D.

FIG. 18 shows the dissolution profiles for chronodosed Ondansetron tablets, 8 mg L-008A to L-008B.

FIGS. 19 and 20 shows dissolution curves in % and mg dissolved, respectively, up to 48 hours combining 36 mg lot L004-04007A with 8 mg lot L004-04002J (chronodosed) within the same vessels for a total of 44 mg instead of 48 mg. The chronodosd contribution to further increase the dissolution after 36 hours can be appreciated versus the plateau observed for the CR formulation.

While the above-identified drawings set forth presently disclosed embodiments, other embodiments are also contemplated, as noted in the discussion. This disclosure presents illustrative embodiments by way of representation and not limitation. Numerous other modifications and embodiments can be devised by those skilled in the art which fall within the scope and spirit of the principles of the presently disclosed embodiments.

DETAILED DESCRIPTION

As used herein the following terms have the definitions set forth below.

“Hydropathy” refers to a scale of solubility characteristics combining hydrophobicity and hydrophilicity of amino acids. More particularly this term refers to a sliding scale, similar to a pH scale, which assigns relative values which represent the relative balance between hydrophobic and hydrophilic components of an amino acid. A typical scale is set forth in Pliska et al., J. Chromatog. 216, 79, 1981, entitled Relative Hydrophobic Character of Amino Acid Side Chains, wherein glycine has a value of 0, representing a relatively equal balance between hydrophobic and hydrophilic components and may be referred to as relatively ‘neutral’, ‘balanced’, ‘slightly hydrophilic’; or ‘weakly hydrophobic’, iso-leucine has a positive value of 1.83 and is strongly hydrophobic, and on the opposite end of the scale, aspartic acid has a negative value of −2.15 and may be characterized as strongly hydrophilic. Such a scale and the hydropathy characteristics described herein are well known and understood by those skilled in the art.

“Monolithic” refers to tablets that do not require multiple layers, special shapes, osmotic compartments and/or specialized coatings, typically without joints or seams, and are capable of being tableted on modern high speed tableting equipment.

The term “bimodal” as used herein refers to bimodal drug release profiles (fast release/slow release).

A “serotonin antagonist” or “5-HT₃ receptor antagonist” refers to a class of medications useful in preventing and relieving nausea and vomiting caused by chemotherapy and anesthesia. It is believed that serotonin antagonists work by blocking the effects of the chemical serotonin, which is produced in the brain and the stomach. 5-HT₃ receptor antagonists efficacious in treating chemotherapy-induced emesis include, but are not limited to, dolasetron, granisetron, ondansetron, palonosetron, tropisetron.

Extended release solid dosage forms are provided. More particularly, the present disclosure relates to extended release bimodal solid dosage forms for the prevention of chemotherapy induced nausea and vomiting. In an embodiment, an extended release solid dosage form includes an internal portion, wherein the internal portion comprises a first dose of ondansetron; a first coating, wherein the first coating directly encapsulates the internal portion of the solid dosage form; a drug layer coating, wherein the drug layer coating directly encapsulates the first coating, wherein the drug layer coating comprises a second dose of ondansetron, wherein the drug layer coating is at least 4%, by weight, of the solid dosage form, wherein the second dose is equal to at least 15%, by weight, of a total dose of the ondansetron in the solid dosage form, and wherein the first dose is equal to the total dose minus the second dose; and a second coating, wherein the second coating directly encapsulates the drug layer coating, wherein the internal portion has solubility in water of X, wherein the first coating, the drug layer coating, and the second coating have solubility in water of at least Y, and wherein X is less than Y. In an embodiment, the extended release solid dosage form is capable of producing a burst of approximately 25% ondansetron, followed by a zero-order release of the remaining ondansetron over a period of between 16-20 hours. In an embodiment, the extended release solid dosage form is capable of producing a burst of approximately 25% ondansetron, followed by a zero-order release of the remaining ondansetron over a period of between 20-30 hours.

Ondansetron

Ondansetron is an effective antiemetic agent that has greatly improved the quality of life of patients undergoing chemotherapy. The usual dose administered to patients ranges between 8 mg and 32 mg per day, administered once a day or in divided doses. Ondansetron displays central and/or peripheral action by preferentially blocking the serotonin 5-HT₃ receptors. Ondansetron hydrochloride (HCl) is the dihydrate, the racemic form of ondansetron. Ondansetron has the empirical formula C18H19N3O.HCl.2H2O, representing a molecular weight of 365.9. Ondansetron HCl dihydrate is a white to off-white powder that is soluble in water and normal saline.

Internal Portion (“Core”) of Solid Dosage Forms of an Embodiment of the Present Disclosure

As a tablet passes through the human digestive tract, it is subjected to pH values ranging from about 1.5 to about 7.4. The saliva of the mouth has a neutral pH, the stomach has a pH varying from about 1.5-4.0, and the pH of the intestines carries a pH between about 5.0-7.5. For a drug to approach zero-order release, the drug's dissolution must be independent of the pH in the surrounding environment. The internal portion (“core”) of a dosage form of the present disclosure may approach zero order delivery of a drug.

Internal Portion—Electrolyte Platform

In an embodiment, the internal portion (“core”) is comprised of a hydrophilic swellable matrix, in which is disposed a pharmaceutically active agent (“API”) and one or more electrolytes. The “electrolyte core” is a slow release (“SR”) formulation. The one or more electrolytes, either in combination with the API or another salt upon reaction in an aqueous medium, causes a hardening reaction of the matrix. The rate of outward diffusion is controlled by exposing the internal portion to an aqueous medium. This in turn causes a hardening reaction to occur in a time dependent manner from the outer boundaries towards the inner boundaries of the internal portion; the hardened reaction product, in turn limits outward diffusion of the API as the inward ingress of aqueous medium causes a progressive hardening from the outer boundaries of the internal portion in a direction towards the inner core there.

The internal portion employs the colloidal chemistry phenomenon of “salting-out” to moderate the swelling and erosion kinetics of a non-ionic polymer matrix containing the API and one or more electrolytes. The presence of these electrolytic compounds in the form of ionizable salts allows for non-collapsible diffusion channels to form; channelization agents used in the past were not ionizable, therefore, the diffusion channels were unpredictable leading to poor release profiles and lack of control. The electrolytes also contribute to a contracting micro-environment within the tablet, whose pH is mediated by the pKa of the electrolyte, thus either enhancing or suppressing the solubility of the API itself. As the matrix hydrates, the electrolytes and polymer compete for water of hydration with the API, resulting in a programmable rate of release. The internal portion is thus capable of zero-order, pH-independent release of an API for up to 24-hours, without regard to the solubility of the API itself.

Through processes of ionic interaction/complexation/molecular and/or self association between a drug and an electrolyte or electrolyte/drug combinations, homogeneously dispersed in a swellable polymer such as hydroxypropylmethylcellulose (HPMC), modify the dynamics of the matrix swelling rate and erosion of the swellable polymer, in accordance with variations in an external pH environment ranging from about 1.5-7.0. These interactions result in controlled matrix hardening. Such hardening is responsible for the control of polymer erosion/dissolution and drug release rates. By design, solvent penetrates the periphery of the tablet and a rapid initial interaction between drug and electrolyte embedded in the polymeric matrix causes immediate hardening of the outer tablet boundary, the rate of hardening consistently decreases toward the center of the matrix core in a time-dependent manner over a long period of time (e.g. 24 hours).

The differential rate of matrix hardening is the driving principle in the internal portion, which is dependent on and controlled by the rate of liquid ingress to the internal portion core. With the simultaneous time-dependent decrease in gel layer integrity, the rate of drug diffusion decreases. This phenomenon compensates for the increase in diffusion path length and decrease in the surface area of the receding core which arises from the swelling property of the polymer. Hence, better controlled, preferably zero order, drug release is achieved. The drug release process can be tailored for up to 24 hours. Control of the changes in core hardness and synchronization of the rubbery/swelling front and described receding phase boundaries as well as erosion of the dissolution front boundary (i.e. erosion of the tablet periphery) results in controlled drug release, preferably including zero order kinetics. Optionally, polymer matrix hardening is also easily achievable through double salt interaction. This binary salt combination is also uniformly dispersed in the polymeric matrix, which through ionic interaction/complexation/molecular and/or self association, increases the relative strength and rigidity of the matrix, resulting in controlled drug release with a similar mechanism to that described above.

One hydrophilic matrix material useful in the internal portion is HPMC K4M. This is a nonionic swellable hydrophillic polymer manufactured by “The Dow Chemical Company” under the tradename “Methocel”. HPMC K4M is also abbreviated as HPMC K4MP, in which the “P” refers to premium cellulose ether designed for controlled release formulations. The “4” in the abbreviation suggests that the polymer has a nominal viscosity (2% in water) of 4000. The percent of methoxyl and hydroxypropyl groups are 19-24 and 7-12, respectively. In its physical form, HPMC K4M is a free-flowing, off-white powder with a particle size limitation of 90%<100 mesh screen. There are other types of HPMC such as K100LVP, K15MP, K100MP, E4MP and E10MP CR with nominal viscosities of 100, 1500, 100000, 4000, and 10000 respectively.

Because the internal portion consists of a non-covalently bonded matrix, the manufacturing process is a fundamentally two-step process of dry-blending and direct compression.

In an embodiment, a salt is dispersed in the matrix at a concentration in the range of about 50% to about 100% by weight of the polymeric matrix. In an embodiment, the salt is selected from one or two members of the group consisting of sodium chloride, sodium bicarbonate, potassium bicarbonate, sodium citrate, sodium bisulfate, sodium sulfite, magnesium sulfate, calcium chloride, potassium chloride, and sodium carbonate.

It is believed that an interaction between drug and salt forms a complex in the surrounding swellable matrix in a layered fashion because it occurs in a time-dependent manner as the solvent media for drug release penetrates the tablet inwardly. Likewise, because the catalyst for the initiation of drug release is liquid ingress, so too is the rate of drug release controlled by the inwardly progressive hardening of the salt complex.

A binary salt system (e.g. calcium chloride and sodium carbonate) may also be used in which case the hardening reaction may be a function of interaction between the salts. Calcium chloride may be incorporated to form a complex with sodium carbonate. With this combination, the reaction products are insoluble calcium carbonate and soluble channel former, sodium chloride. Hence the calcium carbonate embeds itself in the polymer matrix, initiates hardening and slowly dissolves with liquid ingress and the subsequent creation of diffusion channels as drug diffuses out. In a similar way, other binary salt combinations display time-dependent “hardening/de-hardening” behavior.

The amount of salt to be used may be determined taking into consideration the solubility of the drug, the nature of the polymer and the required degree of matrix hardening desired. In case of diltiazem hydrochloride in a HPMC matrix, 100 mg of sodium bicarbonate provides suitable matrix hardening for zero order controlled release, while in the case of the same amount of drug in a different polymer such as polyethylene oxide, 50 mg of sodium bicarbonate appears to be ideal for the attainment of controlled zero order release.

The pharmaceutically active ingredient can be selected from the group consisting of Aprepitant (Emend), Dexamethasone, Dolasetron (Anzemet), Dronabinol (Marinol), Droperidol (Insapsine), Granisetron (Kytril), Haloperidol (Haldol), Methylprednisolone (Medrol), Metoclopramide (Reglan), Nabilone (Cesamet), Ondansetron (Zofran), Palonosetron (Aloxi), Prochlorperazine (Procomp), and pharmaceutically acceptable salts thereof, or combinations thereof.

In an embodiment, the internal portion of a solid dosage form of the present disclosure is a hydrophilic swellable polymeric matrix having dispersed within the matrix a pharmaceutically effective amount of at least one serotonin antagonist whose degree of solubilization is substantially independent of pH over a pH in the range of pH 1.5 to pH 7 0.5 and an inorganic salt, wherein the inorganic salt is present at a concentration in the range of 50% to 100% by weight of the polymeric matrix. In an embodiment, the inorganic salt is sodium citrate. In an embodiment, the hydrophilic swellable polymeric matrix is hydroxypropylmethylcellulose or polyethylene oxide.

An internal portion as described above can be prepared by a process as disclosed in U.S. Pat. No. 6,090,411, which is incorporated herein by reference for the teachings disclosed therein.

Internal Portion—Amino Acid Platform

In an embodiment, the internal portion (“core”) is comprised of a hydrophilic extragranular polymer in which is dispersed a plurality of granules of an API, granulated with at least one amino acid, and an intragranular polymer. The “amino acid core” or “AA core” is a slow release (“SR”) formulation. The granules are dispersed within a hydrophilic extragranular polymer to form a monolithic matrix. The extragranular polymer more rapidly hydrates relative to the intragranular polymer. The rapid hydration of the extragranular polymer assists in the approximation of a linear release profile of the drug and facilitates near 100% dissolution, while extending the duration of release and reducing the burst effect frequently encountered with extended release dosage forms. Although the linear release rate can be tailored to fit the needs of each application by selecting polymers for different dissolution rates, as understood by one of ordinary skill in the art, a release time of 12 to 24 hours is most preferred.

The intragranular polymer is combined with an API, and at least one amino acid to form granules. The intragranular polymer may be one or more of the following: polyvinyl acetate, a galactomannan polysaccharide such as hydroxypropyl guar, guar gum, locust bean gum, pectin, gum acacia, gum tragacanth, karaya gum, cellulose ethers such as hydroxypropylmethyl cellulose (HPMC), as well as other gums and cellulose ethers to be chosen by one of skill in the art for properties consistent with the teaching of this invention. In an embodiment, the intragranular polymer is a galactomannan polysaccharide such as guar gum (with a viscosity range of 75-6000 cps for a 1% solution at 25° C. in water and a particle size 10-300 μm).

The intragranular polymer in the internal portion is present in amounts between 4% and 45% of the total dosage form weight. The specific type of intragranular polymer and amount of intragranular polymer used is chosen depending on the desired rate of drug release, viscosity of the polymer, the desired drug load, and the drug solubility. The intragranular polymer hydrates less rapidly than the extragranular polymer. The relative difference in hydration rates between the two polymers creates a less viscous intragranular polymer and a more viscous extragranular polymer. Over time, the difference in viscosity contributes to the continuous erosion and disintegration of the solid dosage form.

Amino acids are useful in this embodiment for two primary reasons. First, the amino acids are a factor in determining the viscosity of the polymers. As noted above, over time the difference in viscosity between the extragranular and intragranular polymers contributes to the continuous erosion and disintegration of the core, facilitating about 100% release of the drug. Another important aspect of using an amino acid in the granule is that the hydropathy of the amino acid may be exploited to modulate the solubility and release of a drug.

Thus, the amino acid is selected for hydropathy characteristics depending on the solubility characteristics of the active compound. When the compound is at least sparingly water soluble, that is, for example, sparingly soluble, soluble or has a higher level of solubility, as defined by the United States Pharmacopeia, an amino acid is utilized which has a relatively equal balance between hydrophilic and hydrophobic components, i.e. is neutral or balanced or within close proximity to neutrality, or is relatively more strongly hydrophilic.

For example, dissolution and release of soluble or sparingly soluble ionizable drugs such as verapamil HCl can be controlled by the inclusion of one or more amino acids in the granules. Without subscribing to a particular theory of drug release and dissolution, it is believed that the nature of the granulation process is such that as the formulation components come into close molecular contact, granulation reduces the available surface area of the particles, thus reducing the initial rate of hydration. In the granulated formulations, there is sufficient time for the amino acid carboxyl (COOH—) groups and amino groups (NH₂/NH₃₊) to interact with hydroxyl groups on the polymer, thus mediating the swelling, viscosity, and gel properties of the polymer and thereby exerting control on the swelling mediated drug diffusion. Simultaneously, the amino acid carboxyl groups may also interact with suitable polar substituents on the drug molecule such as secondary or tertiary amines. Furthermore, the hydrophilic and ionic nature of amino acids results in their extensive hydration in aqueous solution. Consequently, the amino acid promotes erosion, but also competes with both the polymer and the drug for water uptake necessary for hydration and dissolution.

However, when the active compound is less than sparingly soluble, including active compounds which are slightly soluble to insoluble, a combination of at least two amino acids is utilized, one of which is strongly hydrophobic, the other of which is relatively more hydrophilic than the hydrophobic component, that is, about neutral or balanced to strongly hydrophilic.

The amino acid component of the granules may comprise any pharmaceutically acceptable α-amino or β-amino acids, salts of α- or β-amino acids, or any combination thereof. Examples of suitable α-amino acids are glycine, alanine, valine, leucine, iso-leucine, phenylalanine, proline, aspartic acid, glutamic acid, lysine, arginine, histidine, serine, threonine, cysteine, asparagine, and glutamine. An example of a β-amino acid is β-alanine.

The type of amino acids used in this embodiment of the internal portion can be described as hydrophilic, hydrophobic, salts of hydrophilic or hydrophobic amino acids, or any combination thereof. Suitable hydrophobic amino acids for use include, but are not limited to, iso-leucine, phenylalanine, leucine, and valine. Further, hydrophilic amino acids, such as glycine, aspartate and glutamate can be used in the granule. Ultimately, any amino acid, and any amino acid in combination with another amino acid, can be employed in the present invention to enhance the solubility of a drug. For a detailed list of amino acids that can be used in the present invention and the hydropathy of each, see Albert L. Lehninger et al., Principles of Biochemistry 113 (2nd ed. Worth Publishers 1993).

The type and amount of amino acid may be chosen depending on the desired drug load, desired rate of drug release, and the solubility of the drug. The amino acid in the dosage form is typically between 4% and 45% of the total dosage form weight. However, the amount of amino acid is preferably between 11% and 29% by weight of the total dosage form.

The granules may optionally be blended with a coating material, for example magnesium stearate or other hydrophobic derivatives of stearic acid. The amount of coating material used can vary from 1% to 3% of the total weight of the dosage form. Normally, magnesium stearate is used to facilitate processing, for example as a flow aid, but in the present invention magnesium stearate has the additional benefit of retarding dissolution, due to the hydrophobic nature of the coating material. Therefore, magnesium stearate can be used to further adjust the solubility of the dosage form and further retard drug release from the granules.

To enhance the mechanical properties and/or to influence the drug release rate further, the granules may also contain small amounts of inert pharmaceutical fillers and binders/granulating agents as is conventional to the art. Examples of inert pharmaceutical fillers include: lactose, sucrose, maltose, maltodextrins, dextrins, starch, microcrystalline cellulose, fructose, sorbitol, di- and tri-calcium phosphate. Examples of granulating agents/binders include starch, methylcellulose, hydroxy propyl- or hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose, or poly-vinyl pyrrolidone, gum accacia tragacanth and sucrose. Other suitable fillers may also be employed as understood by one of skill in the art. Depending on the physical and/or chemical properties of the drug, a wet granulation procedure (using either an aqueous or organic granulating fluid) or a dry granulation procedure (e.g. slugging or roller compaction) can be employed.

After the granulation of the pharmaceutically active compound, intragranular polymer, amino acids, and optionally fillers and hydrophobic coating materials, the granule is then blended with and dispersed within an extragranular polymer.

The extragranular polymer may be one or more of the following: polyethylene oxide, a galactomannan polysaccharide such as hydroxypropyl guar, guar gum, locust bean gum, pectin, gum accacia, gum tragacanth, karaya gum, cellulose ethers such as hydroxypropylmethyl cellulose (HPMC), as well as other gums and cellulose ethers to be chosen by one of skill in the art for properties consistent with the teaching of this invention. The extragranular polymer may be a galactomannan polysaccharide such as guar gum (with a viscosity range of 75-6000 cps for a 1% solution at 25° C. in water and a particle size 10-300 μm). As noted above, the extragranular polymer should hydrate rapidly and achieve a high level of viscosity in a shorter period of time relative to the intragranular polymer.

The difference in hydration rates between the extragranular polymer and intragranular polymer is achieved by three principle means, (1) by choosing polymers based on differences in particle size, (2) by choosing polymers based on differences in molecular weight and chemical composition and (3) by choosing polymers based on a combination of (1) and (2). Although this disclosure focuses primarily on polymers chosen for differences in particle size, it is possible to achieve the results of this invention by using an intragranular polymer with a different molecular weight and/or chemical composition than the extragranular polymer. For example, polyethylene oxide may be used as the intragranular polymer and guar gum as the extragranular polymer.

Particle size is another characteristic of commercial guar gum because coarser particles ensure rapid dispersion, while finer particles are ideal for fast hydration. Therefore, in order to achieve the desired result of the present invention. In an embodiment, the finer particles are used for the extragranular polymer and less fine particles are used for the intragranular polymer particles. The brochure by HERCULES Incorporated, entitled “Supercol® Guar Gum, 1997” contains the typical properties of guar gum of different grades and particles sizes. Other rapidly hydrating extragranular polymers which may be used include: polyethylene oxide (PEO), cellulose ethers and polysaccharides such as hydroxypropyl guar, pectin, gum accacia and tragacanth, karaya gum, mixtures of the aforementioned polymers and any other polymers to be chosen by one of skill in the art for properties consistent with the teaching of this invention. The amounts and the types of extragranular polymer are chosen depending on the desired drug load, rate of drug release and drug solubility. A range of about 4-47% (by total tablet weight) of extragranular polymer has been found to be feasible, but a range of about 15%-47% is particularly preferred.

A therapeutic amount of an API, for example up to about 75% of the total dosage form weight, can be included in the internal portion. With this drug load, the internal portion approximates a linear release profile, with a minimal, or elimination of, burst effect. However, if desired by a skilled artisan, the extragranular polymer may contain additional amounts of the pharmaceutically active compound to achieve more rapid drug release or an induced burst effect, as well as contain amino acids to mediate dissolution of the pharmaceutically active compound, as described above.

The tableted oral extended release dosage form optionally may be coated with polymers, plasticizers, opacifiers, and colourants as is conventional in the art.

In an embodiment, the internal portion of a solid dosage form of the present disclosure is (1) a plurality of granules comprising (a) at least one serotonin antagonist; (b) at least one amino acid; and (c) an intragranular polymer; the intragranular polymer comprising 4% to 45% of the total dosage form by weight and, (2) a hydrophilic extragranular polymer in which the granules are dispersed, the extragranular polymer comprising 4% to 47% of the total dosage form by weight and being more rapidly hydrating than the intragranular polymer, wherein the amino acid is selected for hydropathy characteristics depending on solubility characteristics of the at least one serotonin antagonist and comprises 11% to 29% of the total dosage form by weight. In an embodiment, when the at least one serotonin antagonist is at least sparingly soluble in water, the amino acid has a relatively equal balance between hydrophobic and hydrophilic components or is relatively more hydrophilic. In an embodiment, when the at least one serotonin antagonist is less than sparingly soluble in water, the amino acid is a combination of at least two amino acids, one of which is moderately or strongly hydrophobic, the other of which is relatively more hydrophilic. In an embodiment, the intragranular polymer comprises at least one of the following: polyvinyl acetate, a galactomannan polysaccharide selected from the group consisting of hydroxypropyl guar, guar gum, locust bean gum, pectin, gum accacia, tragacanth, karaya gum, or cellulose ethers. In an embodiment, the amino acid is selected from the group consisting of: a) α-amino acids b) β-amino acids c) a combination of α- and β-amino acids. In an embodiment, the α-amino acid is at least one member selected from the group consisting of glycine, alanine, valine, leucine, iso-leucine, phenylalanine, proline, aspartic acid, glutamic acid, lysine, arginine, histidine, serine, threonine, cysteine, asparagine and glutamine. In an embodiment, the combination of α and β amino acids comprises β-alanine and at least one α-amino acid selected from the group consisting of glycine, alanine, valine, leucine, iso-leucine, phenylalanine, proline, aspartic acid, glutamic acid, lysine, arginine, histidine, serine, threonine, cysteine, asparagine, and glutamine. In an embodiment, the amino acid is selected from the group consisting of: a) a balanced amino acid having a relatively equal balance between hydrophobic and hydrophilic components or a relatively more hydrophilic amino acid, or b) a combination of (i) a balanced amino acid or a relatively more hydrophilic amino acid and (ii) a hydrophobic amino acid. In an embodiment, the balanced amino acid comprises glycine. In an embodiment, the internal portion comprises glycine and a hydrophobic amino acid selected from iso-leucine, valine, and phenylalanine. In an embodiment, the plurality of granules are blended with a hydrophobic coating material. In an embodiment, the hydrophobic coating material is magnesium stearate. In an embodiment, the hydrophobic coating material is 1% to 3% of the total dosage form weight.

An internal portion as described above can be prepared by a process as disclosed in U.S. Pat. No. 6,517,868, which is incorporated herein by reference for the teachings disclosed therein.

First and Second Coatings

The first coating and the second coating of an extended release bimodal solid dosage form of the present disclosure are non-functional coatings that act as processing aids. The first coating and the second coating do not substantially affect the release of the API from the dosage form. In an embodiment, the first and the second coating comprise a hydrophilic material. In an embodiment, the hydrophilic material is hypromellose. In an embodiment, the hypromellose is Methocel E5. In an embodiment, the first and the second coating further comprise the coating additive plasACRYL™, an aqueous emulsion of glyceryl monostearate and triethyl citrate (developed by Emerson Resources, Inc. of Norristown, Pa., USA). In an embodiment, the plasACRYL™ used in the first and second coatings is T20 grade. In an embodiment, the PlasACRYL™ T20 is a 20% aqueous suspension, containing an anti-tacking agent, a plasticizer and a stabilizer. Hypromellose is a pH independent non-ionic polymer formed by partial substitution with O-methylated and O-(2-hydroxypropylated) groups. The grades of hypromellose can vary upon extent to substitution which affects the viscosity. HPMC K4M Premium exhibits a viscosity of 3550 mPas, while HPMC E5 premium LV is a low viscosity grade polymer having a viscosity of 5 mPas. Hypromellose is soluble in cold water and forms a colloidal viscous liquid.

Drug Layer Overcoat

The drug layer overcoat of an extended release solid dosage form of the present disclosure is an immediate release (“IR”) drug layer. In an embodiment, the drug layer overcoat is sufficiently designed to yield a burst of about 25% API, which, when the solid dosage form is ingested orally, would result in about 25% API being released in the stomach. In an embodiment, the drug layer overcoat, or immediate release drug layer, comprises ondansetron hydrochloride, hypromellose and plasACRYL™. In an embodiment, the hypromellose used in the IR layer is Methocel E5.

Additional Layers—Enteric Coating

In an embodiment, an extended release solid dosage form of the present disclosure further includes an enteric coating. In an embodiment, an enteric coating layer is positioned between the first coating and the drug layer overcoat. In an embodiment, the enteric coating layer is EUDRAGIT® L30D-55. In an embodiment, the enteric coating layer is EUDRAGIT® FS 30 D. In an embodiment, the enteric coating layer is SURETERIC®.

The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the described invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric.

EXAMPLES Example 1—Formulation Development of 36 to 48 Hour Extended Release Oral Solid Dosage Form of Ondansetron

TABLE 1 Materials Used Product Name (Commercial Name) Function Lot No. Supplier Appearance Ondansetron HCl API A71070812/002 HiKAL Off white powder Methocel K4M premium DC Sustained release YE18012NX2 Colorcon White to off agent white powder Sodium dihydrogen citrate Electrolyte BCBG7557V Sigma White powder anhydrous Microcrystalline Cellulose Filler, C00123/ Blanver/ White powder type 102 (Tabulose-102) Compression Aid C00098 FMC (Avicel PH 102) Biopolymer Lactose monohydrate 80 Filler C00125 Meggle White powder (Tablettose 80) Sodium starch glycolate Disintegrant C00126 Blanver White powder (Explosol) Magnesium stearate Lubricant C00124 Peter Greven White powder (Ligamed MF-2-V) Hypromellose Coating agent 10056/10 JRS Pharma White powder (Vivapharm HPMC E5) Plasacryl T20 (20%) Anti-tacking agent PT110601/ Evonik White emulsion and plasticizer C00174 Eudragit L30 D55 (30%) Coating agent C00127/ Evonik White suspension C00255 Triethyl Citrate Plasticizer C00132 Vertellus Clear liquid Eudragit RS 30D (30%) Coating agent G100518097/ Evonik White suspension G110518108 Eudragit RL 30D (30%) Coating agent G100816150/ Evonik White suspension G111116227 Talc Anti-tacking agent C00037 Talc White to grayish- Luzenac white powder Pharma Purified water Coating diluting N/A Corealis Clear liquid agent Pharma

Tablets Characterization

Measurement of weight: Raw materials composing the core tablet as well as tablets' weight and coating system components weight was carried out using a Mettler Toledo balance model PR5001, AT200 or AG104. Measurement of crushing strength: Crushing strength was determined via a diametral crushing using a Vanderkamp VK 200RC hardness tester. Measurement of thickness: Thickness of tablets was measured via a Mitutoyo model CD-6″ CS. Measurement of disintegration time: The disintegration times were determined according to USP method <701> in purified water at 37° C. using a disintegration bath (Hanson Research, model QC-21, Chatsworth, Calif.). Measurement of friability USP method <1216>: Friability will be evaluated from the percentage weight loss of 6.5 g or more of core tablets tumbled in a friabilator (model EF-2, Electrolab) for 100 rotations at 25 rpm. The tablets will be dedusted, and the loss in weight caused by fracture or abrasion recorded. Friability below 1% is considered acceptable for immediate release oral tablets. In vitro dissolution testing: The dissolution of bimodal developed drug product was conducted according the UV Spectrophotometric Method™ 11-0233PR for Dissolution of Ondansetron Bimodal Enteric Coated Tablets, 24 mg and Ondansetron Enteric Coated Tablets, 18 mg Table 2 presents the dry blend direct compression composition of extended release core tablet formulations 20 mg and 28 mg of ondansetron free base.

TABLE 2 Ondansetron Internal Electrolyte core (“Electrolyte core”) Dry Blend Formulation Prototypes Lab scale L004-04~ 001 003 005 007 (20 mg free base) (28 mg free base) Ingredient Name % (w/w) Ondansetron HCl 6.64 9.30 9.30 9.30 Methocel K4M 26.70 41.30 34.30 30.00 premium DC Sodium 13.35 13.55 13.35 13.35 dihydrogen citrate anhydrous Microcrystalline 52.78 35.52 42.52 46.82 Cellulose type 102 (TABULOSE ®- 102) Magnesium stearate 0.53 0.53 0.53 0.53 (Ligamed MF-2-V) Total 100.0 100.0 100 100.0

Table 3 presents the dry blend direct compression composition of core tablet 8 mg of Ondansetron free base formulation assessed to be chronodosed coated.

TABLE 3 Composition of Dry Blend Direct Compression Core Tablet Formulation Ondansetron to be Chronodosed coated approach Dry Blend Formulation Prototypes Lab scale (8 mg free base) L004-04~ 002 004 006 008 Ingredient Name % (w/w) Ondansetron HCl 12.44 12.44 12.44 12.44 Microcrystalline 87.03 39.03 39.03 39.03 Cellulose type 102 (TABULOSE ®-102) Lactose monohydrate — 48.00 44.00 40.00 80 (TABULOSE ®- 80) Sodium starch — — 4.00 8.00 glucolate (Explosol) Magnesium stearate 0.53 0.53 0.53 1.53 (Ligamed MF-2-V) Total 100.0 100.0 100 100

Example 2—Dry Blending Approach Process Description

A dry blend was processed using a PK Blend Master laboratory blender (Patterson-Kelly, East Stroudsburg, Pa., USA) equipped with 1.5 L V-blender capacity for the laboratory scale formulation L004-04001 to -04008 (Tables 4A and 4B and Tables 5A and 5B respectively). All the materials were screened separately through a 30 mesh hand screen, charged into the V-blender and mixed for 15 minutes at 25 rpm without the lubricant which was then added and mixed for 3 additional minutes. The same blending method was applied to the lots -04002, -04004, -04006 and -04004 intended to be chronodosed coated.

TABLE 4A Extended Release Ondansetron Core Formulation Composition Approach L004-04001, -04001A and -04003 Dry Blend Formulation Prototypes Lab scale L004-04~ 001 (20 mg free base) 003 001 (Low 001A (High (28 mg free base) Ingredient % Batch Hardness) Hardness) % Batch mg/ Name (w/w) size (g) mg/unit (w/w) size (g) unit Ondansetron HCl 6.64 6.64 24.9 9.30 9.30 34.8 Hypromellose 26.70 26.70 100.0 41.30 41.30 154.7 K4M premium DC Sodium 13.35 13.35 50.0 13.55 13.55 50.0 dihydrogen citrate anhydrous Microcrystalline 52.78 52.78 197.6 35.52 35.52 133.0 Cellulose type 102 (TABULOSE ®-102) Magnesium stearate 0.53 0.53 2.0 0.53 0.53 2.0 (Ligamed MF-2-V) Total 100.0 100 374.5 100.0 100.0 374.5

TABLE 4B Extended Release Ondansetron Core Formulation Composition Approach L004-04005, -04007, -04009A and -04009B Dry Blend Formulation Prototypes Lab scale L004-04~ 005 007 009 (28 mg free base) 009A 009B (Low (High Ingredient % Batch mg/ % Batch mg/ % Batch Harness) Harness) Name (w/w) size (g) unit (w/w) size (g) unit (w/w) size (g) mg/unit Ondansetron HCl 9.30 9.30 34.8 9.30 9.30 34.8 9.30 23.25 34.8 Hypromellose 34.30 34.30 128.4 30.0 30.0 112.3 30.0 75.00 112.3 K4M premium DC Sodium 13.35 13.35 50.0 13.35 13.35 50.0 13.35 33.38 50.0 dihydrogen citrate anhydrous Microcrystalline 42.52 42.52 159.2 46.82 46.82 175.3 46.82 117.05 175.3 Cellulose type 102 (TABULOSE ®- 102) Magnesium 0.53 0.53 2.0 0.53 0.53 2.0 0.53 1.33 2.0 stearate (Ligamed MF-2- V) Total 100.0 100.0 374.5 100.0 100.0 374.5 100.0 250.0 374.5

TABLE 5A Core Formulation Composition of Ondansetron to be Chronodosed coated approach L004-04002 and -04004 Dry Blend Formulation Prototypes Lab scale (8 mg free base), L004-04~ 002 Low High Hardness Hardness 004 Ingredient % Batch 002 002C % Batch (mg/ Name (w/w) size (g) (mg/unit) (w/w) size (g) unit) Ondansetron HCl 12.44 12.44 9.95 12.44 12.44 9.95 Microcrystalline 87.03 87.03 69.6 39.03 39.03 31.2 Cellulose type 102 (Tabulose-102) Lactose — — — 48.00 48.00 38.4 monohydrate 80 (TABLETOSSE ® 80) Sodium starch — — — — — — glucolate (Explosol) Magnesium 0.53 0.53 0.4 0.53 0.53 0.4 stearate (Ligamed MF-2-V) Total 100.0 100.0 80.0 100.0 100.0 80.0

TABLE 5B Core Formulation Composition of Ondansetron to be Chronodosed coated approach L004-04006 and -04008 Dry Blend Formulation Prototypes Lab scale (8 mg free base), L004-04~ 006 008 Ingredient % Batch (mg/ % Batch (mg/ Name (w/w) size (g) unit) (w/w) size (g) unit) Ondansetron HCl 12.44 12.44 9.95 12.44 12.44 9.95 Microcrystalline 39.03 39.03 31.2 39.03 39.03 31.2 Cellulose type 102 (Tabulose-102) Lactose 44.00 44.00 35.2 40.00 40.00 32.0 monohydrate 80 (TABLETOSSE ® 80) Sodium starch 4.00 4.00 3.2 8.00 8.00 6.4 glucolate (Explosol) Magnesium 0.53 0.53 0.4 0.53 0.53 0.4 stearate (Ligamed MF-2-V) Total 100.0 100.0 80.0 100.0 100.0 80.0

The extended release bimodal tablet and chronodosed formulations processes flow are presented in FIG. 1 and FIG. 2 respectively.

Example 3—Core Tablet Compression Approach Process Description

The compression trials of lots L004-04001, -04001A, -04005 and -04007 extended release formulation were performed using a hydraulic laboratory hand press with 10.0 mm diameter standard concave round tooling while the lot -04003 the compression was conducted using a 6 stations rotary tablet press machine type PR6 (SVIAC, Antony, France) equipped with a gravity powder feeder with 8.0×16.0×2.0 deep oval concave ‘D’ type tooling. The core tablets -04007B were also compressed using 6 stations rotary tablet press machine type PR6 with 7.0×14.0 mm ‘D’ type tooling model capsule with the number “20” embedded in upper punch. The core tablets L004-04002, -04002C, -04004, -04006 and -04008 intended to be chronodosed coated were also compressed using also the SVIAC with 6.0 mm round standard concave ‘D’ type tooling.

Example 4—Coating for Tablets

Seal, enteric and immediate release layer coating for bimodal drug product from formulations L004-04001, -04001A, -04003, -04007A, -04007B, -04009A and -04009B as well as for chronodosed film coating for drug products from formulation -04002, -04004, -04006 and -04008 were performed using an Aeromatic-Fielder fluid bed laboratory unit (model Strea-1, Columbia, Md., USA) equipped with a Wurster column. The coating suspensions were sprayed using a Cole-Parmer peristaltic pump (model 77521-40, Vernon Hills, Ill., USA) with Masterflex tubing #16.

Aqueous coating composition for the seal and enteric coat, as well as for the immediate release layer applied on sustained release enteric coated tablets can be found in Tables 6, 7 and 8 respectively. The core tablets 28 mg from the first compression trial of extended release formulation -04005 were not coated. They were intended to evaluate and compare the dissolution profile in pH 6.8 medium against those of -04003.

TABLE 6 Composition of All Seal Coats Aqueous Suspensions Total quantity prepared (g) Lot L004-04 001, 001A, 003, 007A and 009A and Component Supplier Appearance % w/w 007B 009B Purified water* Corealis Clear liquid 93.4 93.4 186.8 Pharma Hypromellose JRS Pharma White powder 6.0 6.0 12.0 (METHOCEL ™ E5) plasACRYL ™ T20 Evonik White emulsion 0.6 0.6 1.2 (20%) TOTAL 100.0 100 200 *Removed during coating and drying process

TABLE 7 Composition of All Enteric Coats Aqueous Suspensions Total quantity prepared (g) Lot L004-04 001, 001A, 003, 007A, 007B, 009A Component Supplier Appearance % w/w and 009B Purified water* Corealis Clear liquid 17.02 17.02 Pharma EUDRAGIT ® Evonik White 71.22 71.22 L30 D55 (30%) uspension plasACRYL ™ Evonik White 10.68 10.68 T20 (20%) emulsion Triethyl Citrate Vertellus Clear liquid 1.08 1.08 TOTAL 100 100.0 *Removed during coating and drying process

TABLE 8 Composition of All Immediate Release Layers Aqueous Suspensions Total quantity prepared (g) Lot L004-04 007A 009A and and Component Supplier Appearance % w/w 001 001A 003 007B 009B Purified water* Corealis Clear liquid 93.1 186.2 279.3 Pharma Ondansetron HCl/API HiKAL Off white powder 2.4 4.8 7.2 Hypromellose JRS White powder 3.6 7.2 10.8 (METHOCEL ™ E5) Pharma plasACRYL ™ T20 Evonik White emulsion 0.9 1.8 2.7 (20%) TOTAL 100.0 200.0 300 *Removed during coating and drying process

Table 9 displays different composition of diverse chronodosed aqueous coat suspension trials applied on the 8 mg core tablet. The coat suspension trials #1 and #2 were formulated without talk. Trials #3, #4, #7 and #9 included 5.88% of talk while for the trials #5 and #6, the talc ratio was reduced down to 1%. A mixture of Eudragit® polymers (a methacrylic acid-alkyl acrylate copolymer) was tested. In an embodiment, the Eudragit® polymers are selected from the group consisting of methacrylic acid-alkyl acrylate copolymers with alkaline groups, such as Eudragit® RL and RS polymers. In an embodiment, a mixture of Eudragit® RL and Eudragit® RS is used. In an embodiment, the ratio of Eudragit® RS to Eudragit® RL is 8 to 2. In an embodiment, the ratio of Eudragit® RS to Eudragit® RL is 6 to 4. In an embodiment, the ratio of Eudragit® RS to Eudragit® RL is 7 to 3.

TABLE 9 Various Compositions of Chronodosed Aqueous Suspension Trials #1 to #8 (Eudragit RS/RL ratio) (3-7): (7-3): (9-1): (8-2): (8-2): (6-4): (7-3): (6-4): Trial #1 Trial #2 Trial #3 Trial #4 Trial #5 Trial #6 Trial #7 Trial #8 Component % w/w Purified water* 19.4 19.4 52.55 52.55 41.12 41.12 52.55 52.55 EUDRAGIT ® RS 24.0 56.0 35.29 31.38 44.42 33.32 27.44 23.53 30D (30%) EUDRAGIT ® RL 56.0 24.0 3.93 7.84 11.11 22.21 11.78 15.69 30D (30%) plasACRYL ™ T20 0.6 0.6 — — — — — — (20%) Tri ethyl citrate — — 2.35 2.35 2.35 2.35 2.35 2.35 Talc — — 5.88 5.88 1.00 1.00 5.88 5.88 TOTAL 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 Total of Solids (%) 24.12 20.0

Example 5—Tablets Seal Coating

The seal aqueous coating solution of 6.12% w/w was manufactured by dissolving the METHOCEL™ E5 in water, then adding the plasACRYL™ using a marine propeller (≈50.0 mm of diameter) as shown in FIG. 3. Table 10 presents the seal coating process parameters. During the final drying stage, the inlet air temperature was set at 46° C.

TABLE 10 Aeromatic-Fielder fluid bed Seal Coating Process Parameters Tablets Targeted pre Outlet Air Atomizing Tablets Lot Weight warm Coating Inlet Air Temperature Spray Air Air Drying L004- Gain Time Time Temperature (45 ± 5) Rate Pressure Flow Time 04~ (% w/w) (Min) (min) (° C.) (° C.) (g/min) (bar) (m³/h) (Min) 001 2.5% 2 17 59-61 46-50 2.5 1.2 115-130 3 001A 18 58-61 50 2.4 120-130 003 13 58-61 48-50 3.4 110-130 007A 16 58-63 48-51 2.8 125-130 007B 21 58-60 49-50 2.2 130 009A 23 56-58 48-50 2.3 120-125 009B 22 58 48-51 2.4 120

Example 6—Tablets Enteric Coating

A 24.58% w/w aqueous enteric coating system was used and prepared by mixing the water, triethyl citrate and plasACRYL™ using also a marine propeller (≈50.0 mm of diameter) as shown in FIG. 4. The EUDRAGIT® dispersion was added; the suspension was mixed for 30 minutes at 400 rpm then screened through a 60 mesh screen. The enteric coating parameters are reported in Table 11. During the final drying stage, the inlet air temperature was set at 46° C.

TABLE 11 Aeromatic-Fielder fluid bed Enteric Coating Process Parameters Tablets Targeted pre Outlet Air Atomizing Tablets Lot Weight warm Coating Inlet Air Temperature Spray Air Air Drying L004- Gain Time Time Temperature (41 ± 5) Rate Pressure Flow Time 04~ (% w/w) (Min) (min) (° C.) (° C.) (g/min) (bar) (m³/h) (Min) 001 10% 2 18 49-54 43-45 2.1 1.2 110-130 3 001A 13 51-53 43-44 2.9 125-130 003 13 52-53 43-45 2.7 110-120 007A 15 52-55 44-46 2.5 120-130 007B 18 51-53 43-46 2.2 110 009A 18 53-54 43-46 2.0 110 009B 17 53 43-45 2.2 110

Example 7—Tablets Immediate Release Coating

A 6.18% w/w aqueous active suspension was prepared by first dissolving the METHOCEL™ E5 in water half of water to be used, and separately dispersing the ondansetron in water into the remaining water and stirring at high speed (750-950 rpm) using the 50.0 mm diameter marine propeller for 90 minutes. The METHOCEL™ solution was then added to the drug suspension, and finally the plasACRYL™ was added as presented in FIG. 5. The enteric coating parameters are reported in Table 12. During the final drying stage, the inlet air temperature was set at 46° C. for -04001 and maintained at 56-58° C. for -04001A and -04003 as well as subsequent bimodal tablets formulations.

TABLE 12 Aeromatic-Fielder fluid bed Immediate Release Layer Coating Process Parameters Tablets Targeted pre Outlet Air Atomizing Tablets Lot Weight warm Coating Inlet Air Temperature Spray Air Air Drying L004- Gain Time Time Temperature (43 ± 5) Rate Pressure Flow Time 04~ (% w/w) (Min) (min) (° C.) (° C.) (g/min) (bar) (m³/h) (Min) 001 6.02 2 23 57 44-47 4.1 1.2 125-130 3 001A 6.01 24 54-56 45-48 3.9 130 5 003 6.01 26 53-58 44-46 3.6 120-130 007A 6.02 28 55-58 45-47 3.6 120-130 007B 6.13 36 54-56 44-46 2.8 1.2-1.3 110-130 009A 6.06 37 58-61 47-48 2.7 1.3-1.4 120-130 009B 5.75 33 58-60 47-48 3.0 1.4  80-130

Example 8—Tablets Chronodosed Coating

Different chronodosed aqueous suspension compositions were tried at various tablet weight gain to evaluate how long they could delay time of drug product liberation.

For coating chronodosed aqueous suspension compositions (24.12% w/w) used for trials #1 and #2 (FIG. 6), the EUDRAGIT® RL 30D followed by plasACRYL™ were introduced into suitable container and then mixed to form a vortex using the 50.0 mm diameter marine propeller. The EUDRAGIT® RS 30 and purified water were thereafter added sequentially and mixed before sieving over a 250 micron screen (60 mesh).

For coating chronodosed aqueous suspension compositions (20.0% w/w) used for trials #3 to #8 (FIG. 7), the purified water was introduced into a suitable container and stirred using the 50.0 mm diameter marine propeller to form a vortex. The talk and triethyl citrate were then added successively and stirred. Finally, the EUDRAGIT® RS 30D and RL 30D were added and mixed before sieving over a 500 micron screen (35-mesh sieve).

The Table 13 presents chronodose coating parameters. From the chronodosed drug product L004-04002D to -04008B, a curing process step by spraying a few amount of purified water equivalent to around a quarter of total chronodosed aqueous suspension applied or to half (when very few quantity of chronodosed aqueous was applied) at 50° C. outlet temperature was added immediately before final drying phase as recommended by Eudragit Evonik supplier. However, for 04006E and 04008A, the curing step was not performed to evaluate the impact of curing on coated tablets.

TABLE 13 Aeromatic-Fielder fluid bed Chronodose Formulations' Coating Process Parameters Tablets Curing time Targeted pre Inlet Atomizing (Min)/ Tablets Lot Weight warm Coating Air Outlet Spray Air Air Quantity Drying L004- Gain Time Time T Air T Rate Pressure Flow of water Time 04~ Trial (% w/w) (Min) (min) (° C.) (NMT30° C.) (g/min) (bar) (m³/h) sprayed (g) (Min) 002A #1 12.6 2 19 32-35 28-30 1.5 1.2 130 NA 3 002B #2 12.6 29 33-35 29-30 1.4 130 NA 002D #1 25.0 32 34-36 29-30 1.8 1.2-1.3 120-130 8/15  5 002E #2 25.0 37 34-37 30 1.6 1.2-1.3 100-125 11/15  002F #3 30.0 48 36 30-31 2.0 1.2 100-120 12/23.0 002G #4 12.5 13 35-36 29-30 2.9 110-115 3/8  002H (12.5) + 5.0  (13) + 5 35 30 2.8 100 3/6.1 002I (12.5 + (13 + 34-36 28-30 2.8 100-120 3/6.1 5.0) + 5.0 5) + 5 002J  5.0 5 34-36 29-30 2.7 120 3/6.1 004A #5  5.0 6 35-36 29-30 2.4 110 3/6.1 004B (5.0) + 5.0 6 34-35 29-30 2.4 110 3/6.1 004C #6  5.0 6 34-36 29-30 2.4 110-120 4/6.1 004D (5.0) + 5.0 7 32-35 29-30 2.2 120 4/7.2 006A #4  5.0 5 34-36 29-30 2.8 120-130 3/7.0 006B (5.0) + 5.0 6 34-36 30 2.4 130 3/7.1 006C #7  5.0 6 35-36 29-31 2.4 120 4/7.0 006D (5.0) + 5.0 6 35-36 29-30 2.4 110-130 5/7.1 006E #8 10.0 20 34-35 30 1.4 110 NA 006F  6/14.0 008A 10.0 19 35-36 29-31 1.6 115 NA 008B  6/15.2

Example 9—Chronodosed Tablets Extra Curing

The chronodosed tablets lots L004-04002D and -04002F (8 mg Ondansetron free base) were further cured without spraying water for 2 hours at 50° C. inlet air temperature to give respectively L004-04002D-04002HC (2 Hours Cured) and 04002F-04002HC in order to evaluate the extended cured impact on dissolution of chronodose tablets.

The dry blend DC of extended release core tablet formulation L004-04001, -04003, -04005 and -04007 were prepared with 6.64% and 9.30% of API load respectively while the chronodose core formulation 04002, 04004, 04006 and 04008 was manufactured with 12.44% of API load. All the formulations generated a high yield of 99.6% or more from laboratory batches size of 0.1 kg.

Tables 14 and 15 summarizes embodiments of different formulations developed.

TABLE 14 Summary of Bimodal Formulations - First Component of a Pharmaceutical Formulation of the Present Invention It the core Amount of coated Is an enteric Ondansetron Amount of with a seal coat present? HCL in IR layer Ondansetron coat? HPMC Eudragit (mg) & seal coat Lot # HCL in core E5/PlasAcryl L30/PlasAcryl HPMC L004- (mg) T20 T20 E5/Plasacryl T20 04001 20 Yes Yes 8 04001A 20 Yes Yes 8 04003 28 Yes Yes 8 04005 28 No No 0 - No IR layer 04007 28 Yes Yes 8 04007A 28 Yes Yes 8 04007B 28 Yes Yes 8 04009A 28 Yes Yes 8 04009B 28 Yes Yes 8

TABLE 15 Summary of Chronodosed Formulations 0 - Second Component of a Pharmaceutical Formulation of the Present Invention Is the core coated Amount of with Eudragit Ondansetron RS/RL 30 D Lot # HCL in core (chronodosed L004- (mg) coating) 04002A 8 Yes 04002B 8 Yes 04002C 8 Yes 04002D 8 Yes 04002E 8 Yes 04002F 8 Yes 04002G 8 Yes 04002H 8 Yes 04002I 8 Yes 04002J 8 Yes 04004A 8 Yes 04004B 8 Yes 04004C 8 Yes 04004D 8 Yes 04006A 8 Yes 04006B 8 Yes 04006C 8 Yes 04006D 8 Yes 04006E 8 Yes 04006F 8 Yes 04008A 8 Yes 04008B 8 Yes

Example 10—In-Vitro Dissolution Profiles

FIG. 8 presents comparison dissolution profiles of Ondansetron bimodal round convex 28 mg tablets lots -04001 and -04001A compressed at low and high hardness respectively, and the oval convex tablets 36 mg lot -04003. The bimodal 36 mg tablet -04003 with 41.30% of Hypromellose K4M (sustained release agent) gave 80% dissolution at the 36^(th) hour.

The core 28 mg tablet -04005 with reduced sustained release agent down to 34.30% gave 87% dissolution at the 36^(th) hour (FIG. 9). Lots -04007A and -04007B (FIGS. 10 and 11) were formulated with 30.0% of Methocel K4M (sustained release agent). FIG. 10 presents comparison dissolution profiles of Ondansetron core tablets -04007 28 mg and bimodal -04007A. It appeared that the coating had a real impact on dissolution profiles.

FIG. 11 presents comparison dissolution profiles in mg of Ondansetron bimodal from formulations -04001, -04003, and -04007. Drug products -04001, -04001A and -04007A were compressed with 10.0 mm round convex standard toolings while the lot -04003 was compressed with Oval, concave, (8.0×16.0×2.0 mm) and the lot -04007B with Oblong, Capsule, (7.0×14.0 mm upper Emb. “20”).

At the 36 hours of dissolution time, lots 04007A (24.4 kP hardness value) and -04007B (20.2 kP hardness value) showed the highest API mg dissolved slightly over 30 mg out of 36 mg expected. However, lot -04007B showed faster dissolution profile compared to that of -04007A.

FIG. 14 presents comparison dissolution profiles in percentage of Ondansetron bimodal from formulations showed above in FIG. 11 with corrected values of the expected results taking into consideration the actual average core tablet weight of 360.0 mg.

Lot -04009A (with 12.6 kP hardness value) and 04009B (16.7 kP hardness value) were compressed using oval concave new toolings (7.6×14.0 mm) with an average core tablet weight of 376.40 mg and to 386.87 mg respectively. For a hardness difference of only around 4 kP, the compression force increased five times from 400 Kgf to 2200 Kgf for lots 04009A and 04009B, respectively, suggesting a plastic deformation of the tablet core at higher hardness that could explain the faster release. FIG. 12 presents the dissolution profiles in mg/time of the bimodal drug products 04003, 04007A, 04007B, 04009A and 04009B. More than 32 mg out of 36 mg expected were recovered from bimodal tablet 04009B, slightly better than the lot 04007B but a little bit faster. FIG. 13 shows same results in percentage dissolved.

FIG. 15 presents comparison dissolution profiles of chronodosed round convex tablets, 8 mg *04002D and *04002D-04002HC using coating composition trial #1 (EUDRAGIT® RS/RL ratio: 3-7); -04002E using coating composition trial #2 (EUDRAGIT® RS/RL ratio: 7-3), -04002F using coating composition trial #3 (EUDRAGIT® RS/RL ratio: 9-1) and -04002J using coating composition trial #4 (EUDRAGIT® RS/RL ratio: 8-2). The formulation -04002 was formulated with only MCC-102 as filler and showed a core disintegration time over 15 minutes.

The chronodosed coat compositions trials #1 and #2 without talk failed to hold back the dissolution during the 2 hours of acid stage. Contrary to what was expected, an extra curing of two hours for 04002D-04002HC did not improve the acid stage resistance. However, the 2 hour-cured 04002F-04002HC using coating composition trial #3 containing 5.9% of talk (EUDRAGIT® RS/RL ratio: 9-1) was still intact after 36 hours releasing around 1% only. The lot 04002J chronodose coated with 4.9% weight gain using coating composition trial #4 (EUDRAGIT® RS/RL ratio: 8-2 with 5.9% showed very slight release of API over 36 hours.

FIG. 16 displays comparison dissolution profiles of chronodosed round convex tablets, 8 mg from formulation -04004 prepared with MCC-102 and Tablettose 80 with a core disintegration time less than 8 minutes. The lots -04004A and -04004B were chronodose coated using coating composition trial #5 (EUDRAGIT® RS/RL ratio: 8-2 and 1% of talk) for a weight gain of 4.9 and 11.0% respectively while the lots -04004C and -04004D were coated using coating composition trial #6 (EUDRAGIT® RS/RL ratio: 6-4 with 1% of talk) with a weight gain of 4.9 and 10.1%. All the four lots showed a fast dissolution profiles during the first 3 hours but failed to release more than 75% over 36 hours. For an unknown reason, the lot -04004D with double weight gain compared to the lot -04004C showed faster dissolution profile.

FIG. 17 displays comparison dissolution profiles of chronodosed round convex tablets, 8 mg from formulation -04006 prepared with MCC-102, TABLETOSSE® 80 and 4% of sodium starch glycolate as disintegrant and whose core disintegration time was less than 2 minutes. The lots -04006A and -04006B were chronodose coated using coating composition trial #4 as per -04002J, (EUDRAGIT® RS/RL ratio: 8-2 and 5.9% of talk) for a weight gain of 4.8 and 9.8% respectively while the lots -04006C and -04006D were coated using coating composition trial #7 (EUDRAGIT® RS/RL ratio: 7-3 with 5.9% of talk) with a weight gain of 4.9 and 9.8%. The maximum API released over 36 hours was 40% for -04006C.

FIG. 18 displays comparison dissolution profiles of chronodosed round convex tablets, 8 mg from formulation -04008 prepared same excipient as per -04006 but with increased sodium starch glycolate up to 8% and for which the core disintegration time was less than 1 minutes.

The lots 04008A and -04008B were chronodose coated using coating composition trial #8 (EUDRAGIT® RS/RL ratio: 6-4 and 5.9% of talk) for a weight gain of 10.1%. The only difference between both lots in formulation process was that the lot -04008A was not cured after chronodose film coating. The dissolution profiles of both lots were almost similar. When compared to the of -04006D (with similar weight gain but coated using coating composition trial #7 (EUDRAGIT® RS/RL ratio: 7-3 and 5.9% of talk), dissolution profile improved but still not reached over 40% over 36 hours.

A pharmaceutical formulation of the present invention combines a first component selected from the group consisting of lots L004-04001, -04001A, -04003, -04007, -04007A, -04007B, -04009A, -04009B) with a second component selected from the group consisting of lots L004-04002A, -04002B, -04002C, -04002D, -04002E, -04002F, -04002G, -04002H, -04002I, -04002J, -04004A, -04004B, -04004C, -04004D, -04006A, -04006B, -04006C, -04006D, -04006E, -04006F, -04008A, -04008B) to result in a multi-phase product.

In an embodiment, a pharmaceutical formulation of the present invention combines lot L004-04007A with lot L004-04002J to result in a multi-phase product. FIGS. 19 and 20 show dissolution curves in % and mg dissolved, respectively, up to 48 hours combining 36 mg lot L004-04007A with 8 mg lot L004-04002J within the same vessels for a total of 44 mg instead of 48 mg. The chronodose contribution to further increase the dissolution after 36 hours can be appreciated versus the plateau observed for the CR formulation.

In an embodiment, a pharmaceutical formulation of the present invention includes a first component and a second component that are compressed together (an over compression). In an embodiment, a pharmaceutical formulation of the present invention includes a first component and a second component that are two separate units. In an embodiment, the pharmaceutical formulation is a granule or a microgranule. In an embodiment, the pharmaceutical formulation is a sachet. In an embodiment, the pharmaceutical formulation is a tablet or a mini-tablet. In an embodiment, the pharmaceutical formulation is a capsule. In an embodiment, the pharmaceutical formulation is a pellet or micropellet. In an embodiment, the single dosage form is a caplet or a mini-caplet. In an embodiment, the pharmaceutical formulation is a suppository.

Example 11—(Prophetic) In Vivo Testing of Solid Dosage Forms

A single center, randomized, laboratory-blinded, 4-period, 4-sequence, crossover design study will be carried out in healthy male and female subjects. The following investigational products will be administered under fasting conditions:

-   -   Test 1: 1× Ondansetron 36 mg bimodal tablet (electrolyte core)     -   Test 2: 1× Ondansetron 44 mg bimodal tablet (electrolyte core)     -   Test 3: 1× Ondansetron 48 mg bimodal tablet (electrolyte core)     -   Reference: 3× Zofran® 8 mg tablets (1×8 mg tablet administered         three-times daily, at 8-hour intervals: in the morning following         a 10-hour overnight fast, in the afternoon and in the evening)

Selection of Doses in the Study

The dose is chosen to achieve similar exposure as with the marketed immediate-release formulation (Zofran® 8 mg) when administered three-time daily.

Selection and Timing of Dose for Each Subject

Subjects will fast overnight for at least 10 hours prior to morning drug administration.

Tests 1, 2, 3

-   -   A single dose of the assigned Test formulations will be         administered orally with approximately 240 mL of water at         ambient temperature, starting at 07:30, to one subject per         minute.

Reference

-   -   The assigned Reference formulation will be administered orally         (three-times daily, at 8-hour intervals) with approximately 240         mL of water at ambient temperature, starting at 07:30, to one         subject per minute. Subsequent drug administration will take         place in the afternoon and in the evening at 15:30 and 23:30,         respectively.

Fasting will continue for at least 4 hours following morning drug administration, after which a standardized lunch will be served. The lunch should be completed no later than 5 hours following morning drug administration. All meals will be served at appropriate times thereafter, but not before 9 hours after morning drug administration. The supper will not be served before 11 hours after the morning drug administration and should be completed no later than 13 hours following morning drug administration. Furthermore, a light snack will be completed no later than 13 hours after the morning drug administration. Water will be allowed ad libitum until 1 hour pre-dose and beginning 1 hour after each drug administration.

Efficacy and Safety Measurements Assessed and Flow Chart Pharmacokinetic Assessments

Blood samples for pharmacokinetic measurements will be collected prior to and up to 32 hours (serial sampling) after each morning drug administration. The direct measurements of this study will be the plasma concentrations of ondansetron. These concentrations will be obtained by analysis of the plasma derived from blood samples drawn during this study. The total volume of blood collected per subject (639 mL for males and 653 mL for females) will be considered to have a negligible or no impact on the pharmacokinetic profiles of the drugs and the assessment of bioequivalence. Furthermore, it is considered to have a negligible impact on subjects' safety.

Drug Concentration Measurements

Tests 1-3 (Blood Samples):

-   -   The first blood sample, i.e. the blank plasma sample, will be         collected prior to drug administration while the others will be         collected 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9,         10, 12, 16, 20, 24 and 32 hours after drug administration in one         tube of 6 mL (K₂ EDTA Vacutainers)

Reference (Blood Samples):

-   -   The first blood sample, i.e. the blank plasma sample, will be         collected prior to the morning drug administration while the         others will be collected 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8,         8.25, 8.5, 9, 9.5, 10, 10.5, 11, 12, 14, 16, 16.25, 16.5, 17,         17.5, 18, 18.5, 19, 20, 22, 24, 28 and 32 hours following the         morning drug administration in one tube of 6 mL (K₂ EDTA         Vacutainers). Samples at 8-hour and 16-hour will be collected         within 5 minutes before the drug administration (the afternoon         and evening administrations).

The following pharmacokinetic parameters will be measured:

PARAMETER C_(max) (ng/mL) ln (C_(max)) T_(max) (hours) AUC_(T) (ng · h/mL) ln (AUC_(T)) AUC_(∞) (ng · h/mL) ln (AUC_(∞)) AUC_(T/∞) (%) K_(el) (hours⁻¹) T_(1/2) el (hours) AUC₀₋₂₄ (ng · h/mL) C₂₄ (ng/mL)

Example 12—(Prophetic) 3-Arm Crossover Comparative Bioavailability Study of Solid Dosage Forms

3-arm crossover comparative bioavailability study of five day dosing of solid dosage forms of the present invention once daily versus two day dosing of twice daily ondansetron 8 mg immediate-release tablets versus a single dose of ondansetron 24 mg immediate-release tablets in Healthy Male and Female Volunteers/Fasting State.

Objectives:

The primary objective of this study will be to compare the relative bioavailability and peak and trough concentrations between two FDA approved regimens of commercially available ondansetron 8 mg immediate-release tablet (twice daily Zofran® 8 mg regimen administered for two days and a single dose of Zofran® 24 mg regimen administered as three Zofran® 8 mg tablets taken together), and Test Product 1 of ondansetron 36 mg extended-release tablet of the present invention (administered once daily) and Test Product 2 of a combination of ondansetron 36 mg extended-release component with 8 mg chronodosed component (multi-phase product) of the present invention (administered once daily).

Secondary objectives of the study will be:

-   -   1. To assess the accumulation of ondansetron in the plasma after         dosing with the Test Product for five consecutive daily doses,         under fasting conditions     -   2. To assess the safety and tolerability of the extended-release         formulation on healthy volunteers.

Methodology:

Single center, randomized, open-label, 3-period, 3-sequence, crossover design.

Diagnosis and Main Criteria of Inclusion:

Male and female volunteers, non- or ex-smokers, of at least 18 years of age with a body mass index greater than or equal to 18.50 and below 30.00 kg/m² will be included in the study. Subjects should be in good health as determined by a medical history, complete physical examination (including vital signs), 12-lead Electrocardiogram (ECG) and the usual clinical laboratory tests (general biochemistry, hematology, urinalysis) including negative Human Immunodeficiency Virus (HIV), Hepatitis B and Hepatitis C tests as well as negative urine drug screening of alcohol, cotinine and drugs of abuse and negative beta Human Chorionic Gonadotropin (HCG) qualitative serum pregnancy test (for female subjects).

Test Product 1, Dose and Mode of Administration: Name: Ondansetron

Dosage form/Route of administration: A bimodal tablet of the present invention (Electrolyte CDT Core)/Oral (“Test Product 1”) Regimen for Treatment-1: Single 36 mg dose (1×36 mg) once daily for 5 consecutive days

Test Product 2, Dose and Mode of Administration: Name: Ondansetron

Dosage form/Route of administration: A multi-phase product administered as a capsule, caplet or suppository of the present invention (Electrolyte CDT Core/Chronodosed)/Oral (“Test Product 2”) Regimen for Treatment-1: Single 36 mg dose (1×36 mg) once daily for 5 consecutive days

Reference Product, Dose and Mode of Administration:

-   Name: Zofran® -   Dosage form/Route of administration: Tablet/Oral -   Regimen for Treatment-2: Single 8 mg dose (1×8 mg) twice daily at an     8-hour interval on Day 1 and at a 12-hour interval on Day 2 -   Regimen for Treatment-3: Single 24 mg dose (3×8 mg)

Treatments:

-   Treatment-1: Test administered once daily for 5 consecutive days -   Treatment-2: Reference administered twice daily, at 8-hour intervals     on Day 1 and at 12-hour intervals on Day 2 -   Treatment-3: A single 24 mg dose administered as three Reference     tablets taken together

Duration of Treatment:

-   Treatment-1: A single 36 mg dose of ondansetron (1×36 mg bimodal     tablet (Electrolyte CDT Core)) (“Test Product 1”) will be orally     administered once daily in the morning following a 10-hour overnight     fast for 5 consecutive days. A single 44 mg dose of ondansetron     (1×44 mg multi-phase produce (Electrolyte CDT Core/Chronodosed))     (“Test Product 2”) will be orally administered once daily in the     morning following a 10-hour overnight fast for 5 consecutive days. -   Treatment-2: A single 8 mg dose of Zofran® (1×8 mg tablet) will be     orally administered twice daily, for two consecutive days, at 8-hour     intervals on Day 1 and at 12-hour intervals on Day 2 (first dose in     the morning of each day following a 10-hour overnight fast, and a     second dose in the afternoon (Day 1) or evening (Day 2)) (for a     total of 4 drug administrations). -   Treatment-3: A single 24 mg dose of Zofran® (3×8 mg tablets) will be     orally administered following a 10-hour overnight fast.

The wash-out period between the first drug administrations of each study period will be of 9 calendar days.

Blood Sampling Points:

-   Treatment-1: On Days 1 and 2 of dosing, blood samples will be     collected daily. The first blood sample will be collected prior to     drug administration (within 5 minutes) while the others will be     collected 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16 and 20 hours post drug     administration.     -   On Days 3 and 4 of dosing, blood samples will be collected         daily, the first blood sample will be collected prior to drug         administration (within 5 minutes) while the others will be         collected 2, 4, 6, 8, 10, 14 and 18 hours post drug         administration.     -   On Day 5 of dosing, blood samples will be collected, the first         blood sample will be collected prior to drug administration         (within 5 minutes) while the others will be collected 2, 4, 6,         8, 10, 14, 18, 24 and 48 hours post drug administration. -   Treatment-2: On Day 1 of dosing, blood samples will be collected.     The first blood sample will be collected prior to the morning drug     administration (within 5 minutes) while the others will be collected     1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 14, 16, and 20 hours following     the morning drug administration. The 8-hour blood sample will be     collected within 5 minutes before the afternoon administration.     -   On Day 2 of dosing, blood samples will be collected. The first         blood sample will be collected prior to the morning drug         administration (within 5 minutes) while the others will be         collected 1, 2, 3, 4, 5, 6, 8, 12, 13, 14, 15, 16, 18, 20, 24         and 48 hours following the morning drug administration. The         12-hour blood sample will be collected within 5 minutes before         the evening administration. -   Treatment-3: On Day 1 of dosing, blood samples will be collected.     The first blood sample will be collected prior to the drug     administration (within 5 minutes) while the others will be collected     1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24 and 48 hours following drug     administration.

Criteria for Evaluation Analytical Method:

Analyte: Ondansetron in human plasma Method: HPLC with MS/MS detection Assay range: 0.500 ng/mL to 300.000 ng/mL

Safety:

Safety will be evaluated through assessment of adverse events, standard laboratory evaluations, vital signs, ECG and physical examination.

Mathematical Model and Statistical Methods of Pharmacokinetic Parameters

Main absorption and disposition parameters using a non-compartmental approach with a log-linear terminal phase assumption. Trapezoidal rule to estimate area under the curve, terminal phase estimation based on maximizing the coefficient of determination. The pharmacokinetic parameters of interest for this study will be C_(max) for each day of dosing, AUC₀₋₂₄ for each day of dosing, C_(min) for each day of dosing and C₂₄ for each dosing day. Other parameters including T_(max) for each dosing day, AUC_(T), AUC_(∞), AUC_(T/∞), K_(el) and T_(1/2 el) will be calculated.

Statistical analysis of all pharmacokinetic parameters based on a parametric random ANOVA model. Two-sided 90% confidence interval of the ratio of geometric LSmeans obtained from the ln-transformed pharmacokinetic parameters.

During treatment with the Test products, C_(max) and AUC₀₋₂₄ on Days 2 through 5 will be compared with C_(max) and AUC₀₋₂₄ on Day 1 to assess accumulation with repeated dosing.

Accumulation of the Test formulations will be evaluated using ln-transformed C_(max) and AUC₀₋₂₄. An Analysis of Variance (ANOVA) model will be fitted with the day as a fixed effect and the subject as a random effect.

ANOVA Model for Treatments Comparisons:

-   -   fixed factors: sequence, period, treatment     -   random factor: subject (nested within sequence)

ANOVA for Accumulation:

-   -   fixed factors: day     -   random factor: subject

Standards for Comparative Bioavailability:

Concentrations of ondansetron over time after dosing with the Test formulations will be compared with those after dosing with the reference regimens. A single 24 mg dose of immediate release ondansetron will be considered effective for prevention of nausea and vomiting from highly emetogenic cancer chemotherapy, and twice daily 8 mg dosing will be considered effective for moderately emetogenic chemotherapy. Therefore, if the concentration of ondansetron after dosing with test formulations is found to be similar to or higher than that after dosing with one or both of the reference regimens at most time points over the first 24-hour period studied, one can conclude that the Test products will be at least as effective treatment with the existing regimens for moderately emetogenic cancer chemotherapy.

Safety: Descriptive Statistics.

In an embodiment a pharmaceutical formulation includes (1) a first dosage component comprising: a core comprising a non-ionic polymer matrix providing sustained release, a first amount of ondansetron or an equivalent amount of an ondansetron salt thereof dispersed within the matrix, and an electrolyte dispersed within the matrix; a first seal coat surrounding the core, the first seal coat comprising a non-ionic polymer matrix; and an immediate release drug layer surrounding the first seal coat, wherein the immediate release drug layer comprises a non-ionic polymer and a second amount of ondansetron or an equivalent amount of an ondansetron salt thereof dispersed therein; and (2) a second dosage component comprising: a core comprising a third amount of ondansetron or an equivalent amount of an ondansetron salt thereof, at least one filler, and a lubricant; and a coating surrounding the core, the coating comprising water and a mixture of methacrylic acid-alkyl acrylate copolymers with alkaline groups. In an embodiment, the coating of the second dosage component comprises: from about 30% (w/w) to about 55% (w/w) of purified water; from about 25% (w/w) to about 45% (w/w) of Eudragit® RS 30D; from about 3.0% (w/w) to about 25% (w/w) of Eudragit® RL 30D; and from about 1.0% (w/w) to about 6.0% (w/w) of talc. In an embodiment, the pharmaceutical formulation is sufficiently designed to meet the two stage test dissolution profile in a basket apparatus: (a) release of not more than 25% of the total amount of ondansetron in 2 hours in an acid stage comprising 900 ml 0.1N HCl at 50 rpm; and (b) release of not less than 40% of the total amount of ondansetron in 30 hours in 900 ml phosphate buffer pH 6.8 at 50 rpm following the acid stage.

In an embodiment a packaged pharmaceutical preparation includes a plurality of the pharmaceutical formulations of the present invention in a sealed container and instructions for administering the dosage forms orally to effect prevention of nausea and vomiting

In an embodiment a pharmaceutical preparation includes a plurality of the pharmaceutical formulations of the present invention each in a discrete sealed housing, and instructions for administering the pharmaceutical formulations orally to effect prevention of nausea and vomiting.

In an embodiment a method for reducing side effects of chemotherapy treatment includes administering a pharmaceutical formulation of the present invention to a patient, wherein side effects including nausea and vomiting are reduced after an amount of ondansetron has been released from the pharmaceutical formulation, is absorbed by the patient, and reaches the systemic circulation of the patient.

In an embodiment a pharmaceutical formulation includes a core comprising a non-ionic polymer matrix, a first amount of a first antiemetic drug or a pharmaceutically acceptable salt thereof dispersed within the matrix, and a salt dispersed within the matrix; a first seal coat surrounding the core, wherein the first seal coat is comprised of a non-ionic polymer matrix; and an immediate release drug layer surrounding the first seal coat, wherein the immediate release drug layer comprises a non-ionic polymer and a second amount of a second antiemetic drug or a pharmaceutically acceptable salt thereof dispersed therein, wherein the drug layer is sufficiently designed to release the second amount of the antiemetic drug over a period of at least 1 hour, wherein the pharmaceutical formulation is sufficiently designed to release the first amount of the first antiemetic drug and the second amount of the second antiemetic drug over a minimum period of 16 hours. In an embodiment, the pharmaceutical formulation further includes an enteric coating surrounding the first seal coat. In an embodiment, the pharmaceutical formulation further includes a second seal coat surrounding the immediate release drug layer, wherein the second seal coat is comprised of a non-ionic polymer. In an embodiment, the first seal coat further comprises a coating additive such as plasACRYL™. In an embodiment, the salt in the core is dispersed in the matrix at a concentration in the range of 50% to 100% by weight of the matrix. In an embodiment, upon exposure of the pharmaceutical formulation to an aqueous medium, the salt causes a hardened boundary around the periphery of the matrix, the boundary sequentially progressing inwardly toward the center thereof as the aqueous medium permeates the matrix, the hardened boundary limiting the rate at which the antiemetic drug in the matrix is released from the tablet. In an embodiment, the pharmaceutical formulation is sufficiently designed to release the first amount of the antiemetic drug and the second amount of the antiemetic drug over a minimum period of 20 hours. In an embodiment, the pharmaceutical formulation is sufficiently designed to release the first amount of the antiemetic drug and the second amount of the antiemetic drug over a minimum period of 24 hours. In an embodiment, the first antiemetic drug and the second antiemetic drug are the same drug. In an embodiment, the first antiemetic drug and the second antiemetic drug are each ondansetron or an equivalent amount of an ondansetron salt thereof.

In an embodiment a pharmaceutical formulation includes a core comprising hypromellose, 18 mg of ondansetron or an equivalent amount of an ondansetron salt thereof, and sodium citrate anhydrous; a first seal coat surrounding the core and comprising hypromellose; and an immediate release drug layer surrounding the first seal coat and comprising hypromellose and 6 mg of ondansetron or an equivalent amount of an ondansetron salt thereof, the immediate release drug layer sufficient to release the ondansetron over a period of at least 1 hour, wherein the total amount of ondansetron in the dosage form is released over 24 hours. In an embodiment, the pharmaceutical formulation further includes an enteric coating surrounding the first seal coat. In an embodiment, the pharmaceutical formulation further includes a second seal coat surrounding the immediate release drug layer, wherein the second seal coat is comprised of a non-ionic polymer. In an embodiment, the first seal coat further comprises a coating additive such as plasACRYL™. In an embodiment, the sodium citrate anhydrous in the core is dispersed in the hypromellose at a concentration in the range of 50% to 100% by weight of the hypromellose. In an embodiment, upon exposure of the pharmaceutical formulation to an aqueous medium, the sodium citrate anhydrous causes a hardened boundary around the periphery of the hypromellose, the boundary sequentially progressing inwardly toward the center thereof as the aqueous medium permeates the hypromellose, the hardened boundary limiting the rate at which the ondansetron in the hypromellose is released from the tablet. In an embodiment, when the pharmaceutical formulation is administered to a patient in a fasting state, achieves a C_(max) of at least 50 ng/ml. In an embodiment, when the pharmaceutical formulation is administered to a patient in a fasting state, achieves AUC of at least 600 nghr/ml.

In an embodiment a pharmaceutical formulation includes a core comprising a non-ionic polymer matrix, a first amount of ondansetron or an equivalent amount of an ondansetron salt thereof dispersed within the matrix, and a salt dispersed within the matrix; a first seal coat surrounding the core, wherein the first seal coat is comprised of a non-ionic polymer matrix; and an immediate release drug layer surrounding the first seal coat, wherein the immediate release drug layer comprises a non-ionic polymer and a second amount of ondansetron or an equivalent amount of an ondansetron salt thereof dispersed therein, wherein the pharmaceutical formulation results in an in vitro ondansetron dissolution profile when measured in a type 2 paddle dissolution apparatus at 37° C. in aqueous solution containing distilled water at 50 rpm that exhibits: a) from about 20% to 50% of the total ondansetron is released after two and a half hours of measurement in the apparatus; b) from about 50% to 70% of the total ondansetron is released after five hours of measurement in the apparatus; and c) no less than about 90% of the total ondansetron is released after fifteen hours of measurement in the apparatus. In an embodiment, when the pharmaceutical formulation is administered to a patient in a fasting state at a dose of 24 mg ondansetron, achieves a C_(max) of at least 50 ng/ml. In an embodiment, when the pharmaceutical formulation is administered to a patient in a fasting state at to dose of 24 mg ondansetron, achieves AUC of at least 600 nghr/ml.

In an embodiment a packaged pharmaceutical preparation includes a plurality of any of the pharmaceutical formulations of the present invention in a sealed container and instructions for administering the pharmaceutical formulations orally to effect prevention of nausea and vomiting

In an embodiment a pharmaceutical preparation includes a plurality of any of the pharmaceutical formulations of the present invention each in a discrete sealed housing, and instructions for administering the pharmaceutical formulations orally to effect prevention of nausea and vomiting.

In an embodiment a unit dosage form for oral administration to a patient that is sufficiently designed for preventing nausea and vomiting in the patient, includes a combination of an immediate release ondansetron component containing a unit dosage of ondansetron or a pharmaceutically acceptable salt thereof in the range of 4 mg to 8 mg; and a controlled release ondansetron component containing a unit dosage of ondansetron or a pharmaceutically acceptable salt thereof in the range of 16 mg to 28 mg, the controlled release ondansetron component comprising a non-ionic polymer matrix, the ondansetron within the matrix, and a salt dispersed within the matrix, and wherein the unit dosage form exhibits a maximum plasma concentration (Cmax) at about 2 to about 5 hours (Tmax) after administration and exhibits a comparable Cmax to a non-controlled release ondansetron formulation administered three times per day without decreasing total drug exposure defined by the area under the concentration-time curve (AUC), thereby enabling reduction of concentration-dependent side effects without a decrease in efficacy.

In an embodiment a packaged pharmaceutical preparation includes a plurality of the unit dosage forms of the present invention can be contained within a sealed container and include instructions for administering the dosage forms orally to effect prevention of nausea and vomiting.

In an embodiment a packaged pharmaceutical preparation includes a plurality of the unit dosage forms of the present invention can be contained within a discrete sealed housing and include instructions for administering the dosage forms orally to effect prevention of nausea and vomiting.

In an embodiment a method for preventing nausea and vomiting includes the step of administering a therapeutically-effective amount of a solid oral dosage form or a unit dosage form of the present invention to a patient.

In an embodiment a once-a-day composition includes: (a) a core comprising a non-ionic polymer matrix, a first amount of ondansetron or an equivalent amount of an ondansetron salt dispersed within the matrix, and a salt dispersed within the matrix; (b) a first seal coat surrounding the core, wherein the first seal coat is comprised of a non-ionic polymer matrix; and (c) an immediate release drug layer surrounding the enteric coating, wherein the immediate release drug layer comprises a non-ionic polymer and a second amount of ondansetron or an equivalent amount of an ondansetron salt dispersed therein, wherein the immediate release drug layer is sufficiently designed to release the second amount of ondansetron over a period of at least 1 hour, wherein the immediate release drug layer releases the second amount of ondansetron in the upper gastrointestinal tract of a human patient, wherein the core releases the first amount of ondansetron in the lower gastrointestinal tract of a human patient, wherein the composition is a tablet or capsule that contains 24 to 40 mg of ondansetron or an equivalent amount of an ondansetron salt, and provides an in vivo plasma profile selected from: (a) a mean C_(max) of at least 50.0 ng/ml; (b) a mean AUC₀₋₂₄ of greater than 550.0 nghr/ml; and (c) a mean T_(max) of between approximately 2.0 hours and 5.0 hours. In an embodiment, the once-a-day composition, when administered once-a-day to a human in a fasted state, is bioequivalent to administration to a human in a fasted state, three-times-a-day, a unit dosage form comprising 8 mg ondansetron. In an embodiment, the bioequivalency is established by a 90% Confidence Interval of between 0.80 and 1.25 for both C_(max) and AUC, when administered to a human. In an embodiment, solubility and dissolution characteristics are pH-independent. In an embodiment, the core has a pH-independent dissolution release profile over a pH range of 1.2-6.8. In an embodiment, each of the core and the immediate release drug layer have a pH-independent dissolution release profile over a pH range of 1.2-6.8. In an embodiment, each of the core and the immediate release drug layer are surrounded by a seal coat comprised of a non-ionic polymer which increases hydrophilicity of the composition and as a result the dissolution profile of the composition is pH-independent.

In an embodiment a solid oral dosage form includes: a core comprising hypromellose, 28 mg of ondansetron or an equivalent amount of an ondansetron salt thereof, and sodium citrate anhydrous; a first seal coat surrounding the core and comprising hypromellose; and an immediate release drug layer surrounding the first seal coat and comprising hypromellose and 8 mg of ondansetron or an equivalent amount of an ondansetron salt thereof, the immediate release drug layer sufficient to release the ondansetron over a period of at least 1 hour, wherein the total amount of ondansetron in the dosage form is released over a minimum period of 16 hours. In an embodiment, the solid oral dosage form is sufficiently designed to release the ondansetron over a minimum period of 20 hours. In an embodiment, the solid oral dosage form is sufficiently designed to release the ondansetron over a minimum period of 26 hours. In an embodiment, the solid oral dosage form is sufficiently designed to release the ondansetron over a minimum period of 30 hours. In an embodiment, the solid oral dosage form is sufficiently designed to release the ondansetron over a minimum period of 36 hours. In an embodiment, the solid oral dosage form further comprises an enteric coating surrounding the first seal coat. In an embodiment, the solid oral dosage form further comprises a second seal coat surrounding the immediate release drug layer, wherein the second seal coat is comprised of a non-ionic polymer. In an embodiment, the first seal coat further comprises a coating additive such as plasACRYL™.

In an embodiment a packaged pharmaceutical preparation includes a plurality of the solid oral dosage forms of the present invention can be contained within a sealed container and include instructions for administering the dosage forms orally to effect prevention of nausea and vomiting.

In an embodiment a packaged pharmaceutical preparation includes a plurality of the solid oral dosage forms of the present invention can be contained within a discrete sealed housing and include instructions for administering the dosage forms orally to effect prevention of nausea and vomiting.

In an embodiment a method for preventing nausea and vomiting includes the step of administering a therapeutically-effective amount of a solid oral dosage form of the present invention a patient.

All patents, patent applications, and published references cited herein are hereby incorporated by reference in their entirety. It will be appreciated that several of the above-disclosed and other features and functions, or alternatives thereof, may be desirably combined into many other different systems or application. Various presently unforeseen or unanticipated alternatives, modifications, variations, or improvements therein may be subsequently made by those skilled in the art. 

What is claimed is:
 1. A pharmaceutical formulation comprising: (1) a first dosage component comprising: a core comprising a non-ionic polymer matrix providing sustained release, a first amount of ondansetron or an equivalent amount of an ondansetron salt thereof dispersed within the matrix, and an electrolyte dispersed within the matrix; a first seal coat surrounding the core, the first seal coat comprising a non-ionic polymer matrix; and an immediate release drug layer surrounding the first seal coat, wherein the immediate release drug layer comprises a non-ionic polymer and a second amount of ondansetron or an equivalent amount of an ondansetron salt thereof dispersed therein; and (2) a second dosage component comprising: a core comprising a third amount of ondansetron or an equivalent amount of an ondansetron salt thereof, at least one filler, and a lubricant; and a coating surrounding the core, the coating comprising water and a mixture of methacrylic acid-alkyl acrylate copolymers with alkaline groups.
 2. The pharmaceutical formulation of claim 1 wherein the core of the first dosage component is a compressed core.
 3. The pharmaceutical formulation of claim 1 wherein the core of the second dosage component is a compressed core.
 4. The pharmaceutical formulation of claim 1 wherein the coating of the second dosage component includes a mixture of Eudragit® RS to Eudragit® RL,
 5. The pharmaceutical formulation of claim 4 wherein a Eudragit® RS/Eudragit® RL ratio is 8 to
 2. 6. The pharmaceutical formulation of claim 1 wherein the coating of the second dosage component further includes talc.
 7. The pharmaceutical formulation of claim 1 wherein the coating of the second dosage component comprises: from about 30% (w/w) to about 55% (w/w) of purified water; from about 25% (w/w) to about 45% (w/w) of Eudragit® RS 30D; from about 3.0% (w/w) to about 25% (w/w) of Eudragit® RL 30D; and from about 1.0% (w/w) to about 6.0% (w/w) of talc.
 8. The pharmaceutical formulation of claim 1 wherein the first component and the second component are compressed together.
 9. The pharmaceutical formulation of claim 1 wherein the first component and the second component are two separate units.
 10. The pharmaceutical formulation of claim 1 wherein the first amount of ondansetron is about 20 mg of active free base.
 11. The pharmaceutical formulation of claim 1 wherein the first amount of ondansetron is about 28 mg of active free base.
 12. The pharmaceutical formulation of claim 1 wherein the second amount of ondansetron is about 8 mg of active free base.
 13. The pharmaceutical formulation of claim 1 wherein the third amount of ondansetron is about 8 mg of active free base.
 14. A packaged pharmaceutical preparation comprising a plurality of the pharmaceutical formulations of claim 1 in a sealed container and instructions for administering the pharmaceutical formulations orally to effect prevention of nausea and vomiting.
 15. A packaged pharmaceutical preparation comprising a plurality of the pharmaceutical formulations of claim 1 each in a discrete sealed housing, and instructions for administering the pharmaceutical formulations orally to effect prevention of nausea and vomiting.
 16. A method for preventing nausea and vomiting comprising the step of administering the pharmaceutical formulation of claim 1 to a patient.
 17. The pharmaceutical formulation of claim 1 wherein the single oral dosage form is sufficiently designed to release all of the ondansetron over a minimum period of 36 hours.
 18. The pharmaceutical formulation of claim 1 wherein the single oral dosage form is sufficiently designed to release all of the ondansetron over a minimum period of 40 hours.
 19. The pharmaceutical formulation of claim 1 wherein the single oral dosage form is sufficiently designed to release all of the ondansetron over a minimum period of 44 hours.
 20. The pharmaceutical formulation of claim 1 wherein the single oral dosage form is sufficiently designed to release all of the ondansetron over a minimum period of 48 hours.
 21. The pharmaceutical formulation of claim 1 sufficiently designed to meet the two stage test dissolution profile in a basket apparatus: (a) release of not more than 25% of the total amount of ondansetron in 2 hours in an acid stage comprising 900 ml 0.1N HCl at 50 rpm; and (b) release of not less than 40% of the total amount of ondansetron in 30 hours in 900 ml phosphate buffer pH 6.8 at 50 rpm following the acid stage. 